Andersen, P; Nielsen, MA; Resende, M
Pregnancy-associated malaria is caused by Plasmodium falciparum malaria parasites binding specifically to chondroitin sulfate A in the placenta. This sequestration of parasites is a major cause of low birth weight in infants and anemia in the mothers. VAR2CSA, a polymorphic multi-domain protein o...
Sugiura, Nobuo; Clausen, Thomas Mandel; Shioiri, Tatsumasa; Gustavsson, Tobias; Watanabe, Hideto; Salanti, Ali
Placental malaria, a serious infection caused by the parasite Plasmodium falciparum, is characterized by the selective accumulation of infected erythrocytes (IEs) in the placentas of the pregnant women. Placental adherence is mediated by the malarial VAR2CSA protein, which interacts with chondroitin sulfate (CS) proteoglycans present in the placental tissue. CS is a linear acidic polysaccharide composed of repeating disaccharide units of D-glucuronic acid and N-acetyl-D-galactosamine that are modified by sulfate groups at different positions. Previous reports have shown that placental-adhering IEs were associated with an unusually low sulfated form of chondroitin sulfate A (CSA) and that a partially sulfated dodecasaccharide is the minimal motif for the interaction. However, the fine molecular structure of this CS chain remains unclear. In this study, we have characterized the CS chain that interacts with a recombinant minimal CS-binding region of VAR2CSA (rVAR2) using a CS library of various defined lengths and sulfate compositions. The CS library was chemo-enzymatically synthesized with bacterial chondroitin polymerase and recombinant CS sulfotransferases. We found that C-4 sulfation of the N-acetyl-D-galactosamine residue is critical for supporting rVAR2 binding, whereas no other sulfate modifications showed effects. Interaction of rVAR2 with CS is highly correlated with the degree of C-4 sulfation and CS chain length. We confirmed that the minimum structure binding to rVAR2 is a tri-sulfated CSA dodecasaccharide, and found that a highly sulfated CSA eicosasaccharide is a more potent inhibitor of rVAR2 binding than the dodecasaccharides. These results suggest that CSA derivatives may potentially serve as targets in therapeutic strategies against placental malaria.
Singh, K.; Gittis, A.G.; Nguyen, P.; Gowda, D.C.; Miller, L.H.; Garboczi, D.N. (NIH); (Penn)
Plasmodium falciparum-infected erythrocytes bind to chondroitin sulfate A (CSA) in the placenta via the VAR2CSA protein, a member of the P. falciparum erythrocyte membrane protein-1 family, leading to life-threatening malaria in pregnant women with severe effects on their fetuses and newborns. Here we describe the structure of the CSA binding DBL3x domain, a Duffy binding-like (DBL) domain of VAR2CSA. By forming a complex of DBL3x with CSA oligosaccharides and determining its structure, we have identified the CSA binding site to be a cluster of conserved positively charged residues on subdomain 2 and subdomain 3. Mutation or chemical modification of lysine residues at the site markedly diminished CSA binding to DBL3x. The location of the CSA binding site is an important step forward in the molecular understanding of pregnancy-associated malaria and offers a new target for vaccine development.
Avril, Marion; Hathaway, Marianne J; Cartwright, Megan M; Gose, Severin O; Narum, David L; Smith, Joseph D
VAR2CSA is the main candidate for a vaccine against pregnancy-associated malaria, but vaccine development is complicated by the large size and complex disulfide bonding pattern of the protein. Recent X-ray crystallographic information suggests that domain boundaries of VAR2CSA Duffy binding-like (DBL) domains may be larger than previously predicted and include two additional cysteine residues. This study investigated whether longer constructs would improve VAR2CSA recombinant protein secretion from Pichia pastoris and if domain boundaries were applicable across different VAR2CSA alleles. VAR2CSA sequences were bioinformatically analysed to identify the predicted C11 and C12 cysteine residues at the C-termini of DBL domains and revised N- and C-termimal domain boundaries were predicted in VAR2CSA. Multiple construct boundaries were systematically evaluated for protein secretion in P. pastoris and secreted proteins were tested as immunogens. From a total of 42 different VAR2CSA constructs, 15 proteins (36%) were secreted. Longer construct boundaries, including the predicted C11 and C12 cysteine residues, generally improved expression of poorly or non-secreted domains and permitted expression of all six VAR2CSA DBL domains. However, protein secretion was still highly empiric and affected by subtle differences in domain boundaries and allelic variation between VAR2CSA sequences. Eleven of the secreted proteins were used to immunize rabbits. Antibodies reacted with CSA-binding infected erythrocytes, indicating that P. pastoris recombinant proteins possessed native protein epitopes. These findings strengthen emerging data for a revision of DBL domain boundaries in var-encoded proteins and may facilitate pregnancy malaria vaccine development.
Narum David L
Full Text Available Abstract Background VAR2CSA is the main candidate for a vaccine against pregnancy-associated malaria, but vaccine development is complicated by the large size and complex disulfide bonding pattern of the protein. Recent X-ray crystallographic information suggests that domain boundaries of VAR2CSA Duffy binding-like (DBL domains may be larger than previously predicted and include two additional cysteine residues. This study investigated whether longer constructs would improve VAR2CSA recombinant protein secretion from Pichia pastoris and if domain boundaries were applicable across different VAR2CSA alleles. Methods VAR2CSA sequences were bioinformatically analysed to identify the predicted C11 and C12 cysteine residues at the C-termini of DBL domains and revised N- and C-termimal domain boundaries were predicted in VAR2CSA. Multiple construct boundaries were systematically evaluated for protein secretion in P. pastoris and secreted proteins were tested as immunogens. Results From a total of 42 different VAR2CSA constructs, 15 proteins (36% were secreted. Longer construct boundaries, including the predicted C11 and C12 cysteine residues, generally improved expression of poorly or non-secreted domains and permitted expression of all six VAR2CSA DBL domains. However, protein secretion was still highly empiric and affected by subtle differences in domain boundaries and allelic variation between VAR2CSA sequences. Eleven of the secreted proteins were used to immunize rabbits. Antibodies reacted with CSA-binding infected erythrocytes, indicating that P. pastoris recombinant proteins possessed native protein epitopes. Conclusion These findings strengthen emerging data for a revision of DBL domain boundaries in var-encoded proteins and may facilitate pregnancy malaria vaccine development.
Clausen, Thomas M; Christoffersen, Stig; Dahlbäck, Madeleine
Malaria is a major global health problem. Pregnant women are susceptible to infection regardless of previously acquired immunity. Placental malaria is caused by parasites capable of sequestering in the placenta. This is mediated by VAR2CSA, a parasite antigen that interacts with chondroitin sulfa...
Sugiura, Nobuo; Clausen, Thomas Mandel; Shioiri, Tatsuasa
with chondroitin sulfate (CS) proteoglycans present in the placental tissue. CS is a linear acidic polysaccharide composed of repeating disaccharide units of d-glucuronic acid and N-acetyl-d-galactosamine that are modified by sulfate groups at different positions. Previous reports have shown that placental......-adhering IEs were associated with an unusually low sulfated form of chondroitin sulfate A (CSA) and that a partially sulfated dodecasaccharide is the minimal motif for the interaction. However, the fine molecular structure of this CS chain remains unclear. In this study, we have characterized the CS chain...... that interacts with a recombinant minimal CS-binding region of VAR2CSA (rVAR2) using a CS library of various defined lengths and sulfate compositions. The CS library was chemo-enzymatically synthesized with bacterial chondroitin polymerase and recombinant CS sulfotransferases. We found that C-4 sulfation...
Nicola K Viebig
Full Text Available Infection with Plasmodium falciparum during pregnancy is one of the major causes of malaria related morbidity and mortality in newborn and mothers. The complications of pregnancy-associated malaria result mainly from massive adhesion of Plasmodium falciparum-infected erythrocytes (IE to chondroitin sulfate A (CSA present in the placental intervillous blood spaces. Var2CSA, a member of the P. falciparum erythrocyte membrane protein 1 (PfEMP1 family is the predominant parasite ligand mediating CSA binding. However, experimental evidence suggests that other host receptors, such as hyaluronic acid (HA and the neonatal Fc receptor, may also support placental binding. Here we used parasites in which var2csa was genetically disrupted to evaluate the contribution of these receptors to placental sequestration and to identify additional adhesion receptors that may be involved in pregnancy-associated malaria. By comparison to the wild-type parasites, the FCR3delta var2csa mutants could not be selected for HA adhesion, indicating that var2csa is not only essential for IE cytoadhesion to the placental receptor CSA, but also to HA. However, further studies using different pure sources of HA revealed that the previously observed binding results from CSA contamination in the bovine vitreous humor HA preparation. To identify CSA-independent placental interactions, FCR3delta var2csa mutant parasites were selected for adhesion to the human placental trophoblastic BeWo cell line. BeWo selected parasites revealed a multi-phenotypic adhesion population expressing multiple var genes. However, these parasites did not cytoadhere specifically to the syncytiotrophoblast lining of placental cryosections and were not recognized by sera from malaria-exposed women in a parity dependent manner, indicating that the surface molecules present on the surface of the BeWo selected population are not specifically expressed during the course of pregnancy-associated malaria. Taken
Viebig, Nicola K.; Levin, Emily; Dechavanne, Sébastien; Rogerson, Stephen J.; Gysin, Jürg; Smith, Joseph D.; Scherf, Artur; Gamain, Benoit
Infection with Plasmodium falciparum during pregnancy is one of the major causes of malaria related morbidity and mortality in newborn and mothers. The complications of pregnancy-associated malaria result mainly from massive adhesion of Plasmodium falciparum-infected erythrocytes (IE) to chondroitin sulfate A (CSA) present in the placental intervillous blood spaces. Var2CSA, a member of the P. falciparum erythrocyte membrane protein 1 (PfEMP1) family is the predominant parasite ligand mediati...
Travassos, Mark A; Coulibaly, Drissa; Bailey, Jason A; Niangaly, Amadou; Adams, Matthew; Nyunt, Myaing M; Ouattara, Amed; Lyke, Kirsten E; Laurens, Matthew B; Pablo, Jozelyn; Jasinskas, Algis; Nakajima, Rie; Berry, Andrea A; Takala-Harrison, Shannon; Kone, Abdoulaye K; Kouriba, Bourema; Rowe, J Alexandra; Doumbo, Ogobara K; Thera, Mahamadou A; Laufer, Miriam K; Felgner, Philip L; Plowe, Christopher V
The Plasmodium falciparum erythrocyte membrane protein 1 (PfEMP1) family mediates parasite sequestration in small capillaries through tissue-specific cytoadherence. The best characterized of these proteins is VAR2CSA, which is expressed on the surface of infected erythrocytes that bind to chondroitin sulfate in the placental matrix. Antibodies to VAR2CSA prevent placental cytoadherence and protect against placental malaria. The size and complexity of the VAR2CSA protein pose challenges for vaccine development, but smaller constitutive domains may be suitable for subunit vaccine development. A protein microarray was printed to include five overlapping fragments of the 3D7 VAR2CSA extracellular region. Malian women with a history of at least one pregnancy had antibody recognition of four of these fragments and had stronger reactivity against the two distal fragments than did nulliparous women, children, and men from Mali, suggesting that the C-terminal extracellular VAR2CSA domains are a potential focus of protective immunity. With carefully chosen sera from longitudinal studies of pregnant women, this approach has the potential to identify seroreactive VAR2CSA domains associated with protective immunity against pregnancy-associated malaria. © The American Society of Tropical Medicine and Hygiene.
Gbédandé, Komi; Fievet, Nadine; Viwami, Firmine
Background The antigen VAR2CSA plays a pivotal role in the pathophysiology of pregnancy-associated malaria (PAM) caused by Plasmodium falciparum. A VAR2CSA-based vaccine candidate, PAMVAC, is under development by an EU-funded multi-country consortium (PlacMalVac project). As part of PAMVAC...
Full Text Available Placental malaria caused by Plasmodium falciparum is a major cause of mortality and severe morbidity. Clinical testing of a soluble protein-based vaccine containing the parasite ligand, VAR2CSA, has been initiated. VAR2CSA binds to the human receptor chondroitin sulphate A (CSA and is responsible for sequestration of Plasmodium falciparum infected erythrocytes in the placenta. It is imperative that a vaccine against malaria in pregnancy, if administered to women before they become pregnant, can induce a strong and long lasting immune response. While most soluble protein-based vaccines have failed during clinical testing, virus-like particle (VLP based vaccines (e.g., the licensed human papillomavirus vaccines have demonstrated high efficacy, suggesting that the spatial assembly of the vaccine antigen is a critical parameter for inducing an optimal long-lasting protective immune response. We have developed a VLP vaccine display platform by identifying regions of the HPV16 L1 coat protein where a biotin acceptor site (AviTagTM can be inserted without compromising VLP-assembly. Subsequent biotinylation of Avi-L1 VLPs allow us to anchor monovalent streptavidin (mSA-fused proteins to the biotin, thereby obtaining a dense and repetitive VLP-display of the vaccine antigen. The mSA-VAR2CSA antigen was delivered on the Avi-L1 VLP platform and tested in C57BL/6 mice in comparison to two soluble protein-based vaccines consisting of naked VAR2CSA and mSA-VAR2CSA. The mSA-VAR2CSA Avi-L1 VLP and soluble mSA-VAR2CSA vaccines induced higher antibody titers than the soluble naked VAR2CSA vaccine after three immunizations. The VAR2CSA Avi-L1 VLP vaccine induced statistically significantly higher endpoint titres compared to the soluble mSA-VAR2CSA vaccine, after 1st and 2nd immunization; however, this difference was not statistically significant after 3rd immunization. Importantly, the VLP-VAR2CSA induced antibodies were functional in inhibiting the binding of
Babakhanyan, Anna; Fang, Rui; Wey, Andrew
BACKGROUND: Antibodies (Ab) to VAR2CSA prevent Plasmodium falciparum-infected erythrocytes from sequestrating in the placenta, i.e., prevent placental malaria (PM). The specificity of Ab to VAR2CSA associated with absence of PM is unknown. Accordingly, differences in the specificity of Ab to VAR2......CSA were compared between multigravidae with and without PM who had Ab to VAR2CSA. METHODS: In a retrospective case-control study, plasma collected from Cameroonian multigravidae with (n = 96) and without (n = 324) PM were screened in 21 assays that measured antibody levels to full length VAR2CSA (FV2......), individual VAR2CSA DBL domains, VAR2CSA domains from different genetic backgrounds (variants), as well as proportion of high avidity Ab to FV2. RESULTS: Multigravidae with and without PM had similar levels of Ab to FV2, the six VAR2CSA DBL domains and different variants, while the proportion of high avidity...
Andersson, Anne-Marie C; dos Santos Marques Resende, Mafalda; Salanti, Ali
The malaria parasite Plasmodium falciparum presents antigens on the infected erythrocyte surface that bind human receptors expressed on the vascular endothelium. The VAR2CSA mediated binding to a distinct chondroitin sulphate A (CSA) is a crucial step in the pathophysiology of placental malaria a...
Dechavanne, Sebastien; Sousa, Patrícia M.; Barateiro, André; Cunha, Sónia F.; Nunes-Silva, Sofia; Lima, Flávia A.; Murillo, Oscar; Marinho, Claudio R. F.; Gangnard, Stephane; Srivastava, Anand; Braks, Joanna A.; Janse, Chris J.; Gamain, Benoit; Penha-Gonçalves, Carlos
Plasmodium falciparum infection during pregnancy leads to abortions, stillbirth, low birth weight, and maternal mortality. Infected erythrocytes (IEs) accumulate in the placenta by adhering to chondroitin sulfate A (CSA) via var2CSA protein exposed on the P. falciparum IE membrane. Plasmodium berghei IE infection in pregnant BALB/c mice is a model for severe placental malaria (PM). Here, we describe a transgenic P. berghei parasite expressing the full-length var2CSA extracellular region (domains DBL1X to DBL6ε) fused to a P. berghei exported protein (EMAP1) and characterize a var2CSA-based mouse model of PM. BALB/c mice were infected at midgestation with different doses of P. berghei-var2CSA (P. berghei-VAR) or P. berghei wild-type IEs. Infection with 104 P. berghei-VAR IEs induced a higher incidence of stillbirth and lower fetal weight than P. berghei. At doses of 105 and 106 IEs, P. berghei-VAR-infected mice showed increased maternal mortality during pregnancy and fetal loss, respectively. Parasite loads in infected placentas were similar between parasite lines despite differences in maternal outcomes. Fetal weight loss normalized for parasitemia was higher in P. berghei-VAR-infected mice than in P. berghei-infected mice. In vitro assays showed that higher numbers of P. berghei-VAR IEs than P. berghei IEs adhered to placental tissue. Immunization of mice with P. berghei-VAR elicited IgG antibodies reactive to DBL1-6 recombinant protein, indicating that the topology of immunogenic epitopes is maintained between DBL1-6–EMAP1 on P. berghei-VAR and recombinant DBL1-6 (recDBL1-6). Our data suggested that impairments in pregnancy caused by P. berghei-VAR infection were attributable to var2CSA expression. This model provides a tool for preclinical evaluation of protection against PM induced by approaches that target var2CSA. PMID:27045035
Full Text Available Malaria, caused by the parasite Plasmodium falciparum, is responsible for substantial morbidity, mortality and economic losses in tropical regions of the world. Pregnant women are exceptionally vulnerable to severe consequences of the infection, due to the specific adhesion of parasite-infected erythrocytes in the placenta. This adhesion is mediated by a unique variant of PfEMP1, a parasite encoded, hyper-variable antigen placed on the surface of infected cells. This variant, called VAR2CSA, binds to chondroitin sulfate A on syncytiotrophoblasts in the intervillous space of placentas. VAR2CSA appears to only be expressed in the presence of a placenta, suggesting that its expression is actively repressed in men, children or non-pregnant women; however, the mechanism of repression is not understood. Using cultured parasite lines and reporter gene constructs, we show that the gene encoding VAR2CSA contains a small upstream open reading frame that acts to repress translation of the resulting mRNA, revealing a novel form of gene regulation in malaria parasites. The mechanism underlying this translational repression is reversible, allowing high levels of protein translation upon selection, thus potentially enabling parasites to upregulate expression of this variant antigen in the presence of the appropriate host tissue.
Beaudet, Julie M; Mansur, Leandra; Joo, Eun Ji
expressing VAR2CSA on the erythrocyte surface. This protein adheres to a low-sulfated chondroitin sulfate-A found in placental tissue causing great harm to both mother and developing fetus. In rare cases, the localization of infected erythrocytes to the placenta can even result in the vertical transmission...... placental tissue accessible to parasites in the bloodstream, suggesting it is the primary receptor for parasite infected red blood cells....
Ayres Pereira, Marina; Mandel Clausen, Thomas; Pehrson, Caroline
During placental malaria, Plasmodium falciparum infected erythrocytes sequester in the placenta, causing health problems for both the mother and fetus. The specific adherence is mediated by the VAR2CSA protein, which binds to placental chondroitin sulfate (CS) on chondroitin sulfate proteoglycans......-down experiments using placental extracts from whole placenta or syncytiotrophoblast microvillous cell membranes showed three distinct CSPGs available for VAR2CSA adherence. Further examination of these three CSPGs by immunofluorescence and proximity ligation assays showed that syndecan-1 is the main receptor...... for VAR2CSA mediated placental adherence. We further show that the commonly used placental choriocarcinoma cell line, BeWo, express a different set of proteoglycans than those present on placental syncytiotrophoblast and may not be the most biologically relevant model to study placental malaria. Syncytial...
Pinto, Vera V; Ditlev, Sisse B; Jensen, Kamilla E
In Plasmodium falciparum malaria endemic areas placental malaria (PM) is an important complication of malaria. The recurrence of malaria in primigravidae women irrespective of acquired protection during childhood is caused by the interaction between the parasite-expressed VAR2CSA antigen and chon...
Mao, Yang; Resende, Mafalda; Daugaard, Mads; Riis Kristensen, Anders; Damm, Peter; G. Theander, Thor; R. Hansson, Stefan; Salanti, Ali
During placental malaria, Plasmodium falciparum infected erythrocytes sequester in the placenta, causing health problems for both the mother and fetus. The specific adherence is mediated by the VAR2CSA protein, which binds to placental chondroitin sulfate (CS) on chondroitin sulfate proteoglycans (CSPGs) in the placental syncytium. However, the identity of the CSPG core protein and the cellular impact of the interaction have remain elusive. In this study we identified the specific CSPG core protein to which the CS is attached, and characterized its exact placental location. VAR2CSA pull-down experiments using placental extracts from whole placenta or syncytiotrophoblast microvillous cell membranes showed three distinct CSPGs available for VAR2CSA adherence. Further examination of these three CSPGs by immunofluorescence and proximity ligation assays showed that syndecan-1 is the main receptor for VAR2CSA mediated placental adherence. We further show that the commonly used placental choriocarcinoma cell line, BeWo, express a different set of proteoglycans than those present on placental syncytiotrophoblast and may not be the most biologically relevant model to study placental malaria. Syncytial fusion of the BeWo cells, triggered by forskolin treatment, caused an increased expression of placental CS-modified syndecan-1. In line with this, we show that rVAR2 binding to placental CS impairs syndecan-1-related Src signaling in forskolin treated BeWo cells, but not in untreated cells. PMID:27556547
Yeung Lo Tutterrow
Full Text Available VAR2CSA mediates sequestration of Plasmodium falciparum-infected erythrocytes in the placenta, increasing the risk of poor pregnancy outcomes. Naturally acquired antibodies (Ab to placental parasites at delivery have been associated with improved pregnancy outcomes, but Ab levels and how early in pregnancy Ab must be present in order to eliminate placental parasites before delivery remains unknown. Antibodies to individual Duffy-binding like domains of VAR2CSA have been studied, but the domains lack many of the conformational epitopes present in full-length VAR2CSA (FV2. Thus, the purpose of this study was to describe the acquisition of Ab to FV2 in women residing in high and low transmission areas and determine how Ab levels during pregnancy correlate with clearance of placental parasites. Plasma samples collected monthly throughout pregnancy from pregnant women living in high and low transmission areas in Cameroon were evaluated for Ab to FV2 and the proportion of high avidity Ab (i.e., Ab that remain bound in the presence of 3M NH(4SCN was assessed. Ab levels and proportion of high avidity Ab were compared between women with placental malaria (PM(+ and those without (PM(- at delivery. Results showed that PM(- women had significantly higher Ab levels (p = 0.0047 and proportion of high avidity Ab (p = 0.0009 than PM(+ women throughout pregnancy. Specifically, women with moderate to high Ab levels (>5,000 MFI and those with ≥ 35% high avidity Ab at 5-6 months were found to have 2.3 (95% CI, 1.0-4.9 and 7.6-fold (p = 0.0013, 95% CI: 1.2-50.0 reduced risk of placental malaria, respectively. These data show that high levels of Ab to FV2, particularly those with high avidity for FV2, produced by mid-pregnancy are important in clearing parasites from the placenta. Both high Ab levels and proportion of high avidity Ab to FV2 may serve as correlates of protection for assessing immunity against placental malaria.
Avril, Marion; Kulasekara, Bridget R; Gose, Severin O
Pregnancy-associated malaria (PAM) is characterized by the placental sequestration of Plasmodium falciparum-infected erythrocytes (IEs) with the ability to bind to chondroitin sulfate A (CSA). VAR2CSA is a leading candidate for a pregnancy malaria vaccine, but its large size ( approximately 350 k...
Sander, Adam F; Salanti, Ali; Lavstsen, Thomas
multiple genes coding for different VAR2CSA proteins, and parasites with >1 var2csa gene appear to be more common in pregnant women with placental malaria than in nonpregnant individuals. We present evidence that, in pregnant women, parasites containing multiple var2csa-type genes possess a selective...... advantage over parasites with a single var2csa gene. Accumulation of parasites with multiple copies of the var2csa gene during the course of pregnancy was also correlated with the development of antibodies involved in blocking VAR2CSA adhesion. The data suggest that multiplicity of var2csa-type genes...
Tutterrow, Yeung Lo; Salanti, Ali; Avril, Marion
VAR2CSA mediates sequestration of Plasmodium falciparum-infected erythrocytes in the placenta, increasing the risk of poor pregnancy outcomes. Naturally acquired antibodies (Ab) to placental parasites at delivery have been associated with improved pregnancy outcomes, but Ab levels and how early...... in pregnancy Ab must be present in order to eliminate placental parasites before delivery remains unknown. Antibodies to individual Duffy-binding like domains of VAR2CSA have been studied, but the domains lack many of the conformational epitopes present in full-length VAR2CSA (FV2). Thus, the purpose...... of this study was to describe the acquisition of Ab to FV2 in women residing in high and low transmission areas and determine how Ab levels during pregnancy correlate with clearance of placental parasites. Plasma samples collected monthly throughout pregnancy from pregnant women living in high and low...
Babakhanyan, Anna; Leke, Rose G F; Salanti, Ali
In pregnant women, Plasmodium falciparum-infected erythrocytes expressing the VAR2CSA antigen bind to chondroitin sulfate A in the placenta causing placental malaria. The binding site of VAR2CSA is present in the ID1-ID2a region. This study sought to determine if pregnant Cameroonian women natura...
Thrane, Susan; Janitzek, Christoph M; Agerbæk, Mette Ø
, this difference was not statistically significant after 3rd immunization. Importantly, the VLP-VAR2CSA induced antibodies were functional in inhibiting the binding of parasites to CSA. This study demonstrates that the described Avi-L1 VLP-platform may serve as a versatile system for facilitating optimal VLP......SA-VAR2CSA vaccines induced higher antibody titers than the soluble naked VAR2CSA vaccine after three immunizations. The VAR2CSA Avi-L1 VLP vaccine induced statistically significantly higher endpoint titres compared to the soluble mSA-VAR2CSA vaccine, after 1st and 2nd immunization; however...
Higgins, Matthew K.
A chondroitin sulfate A-binding DBL important in placental malaria has been overproduced, purified and crystallized. Diffraction data were collected to 1.9 Å resolution. The PfEMP1 proteins of the malaria parasite Plasmodium falciparum are inserted into the membrane of infected red blood cells, where they mediate adhesion to a variety of human receptors. The DBL domains of the var2csa-encoded PfEMP1 protein play a critical role in malaria of pregnancy, tethering infected cells to the surface of the placenta through interactions with the glycosaminoglycan carbohydrate chondroitin sulfate A (CSA). A CSA-binding DBL domain has been overproduced in a bacterial expression system, purified and crystallized. Native data sets extending to 1.9 Å resolution have been collected and phasing is under way
Higgins, Matthew K., E-mail: firstname.lastname@example.org [Department of Biochemistry, University of Cambridge, 80 Tennis Court Road, Cambridge CB2 1GA (United Kingdom)
A chondroitin sulfate A-binding DBL important in placental malaria has been overproduced, purified and crystallized. Diffraction data were collected to 1.9 Å resolution. The PfEMP1 proteins of the malaria parasite Plasmodium falciparum are inserted into the membrane of infected red blood cells, where they mediate adhesion to a variety of human receptors. The DBL domains of the var2csa-encoded PfEMP1 protein play a critical role in malaria of pregnancy, tethering infected cells to the surface of the placenta through interactions with the glycosaminoglycan carbohydrate chondroitin sulfate A (CSA). A CSA-binding DBL domain has been overproduced in a bacterial expression system, purified and crystallized. Native data sets extending to 1.9 Å resolution have been collected and phasing is under way.
Morten A Nielsen
Full Text Available The disease caused by Plasmodium falciparum (Pf involves different clinical manifestations that, cumulatively, kill hundreds of thousands every year. Placental malaria (PM is one such manifestation in which Pf infected erythrocytes (IE bind to chondroitin sulphate A (CSA through expression of VAR2CSA, a parasite-derived antigen. Protection against PM is mediated by antibodies that inhibit binding of IE in the placental intervillous space. VAR2CSA is a large antigen incompatible with large scale recombinant protein expression. Vaccines based on sub-units encompassing the functionally constrained receptor-binding domains may, theoretically, circumvent polymorphisms, reduce the risk of escape-mutants and induce cross-reactive antibodies. However, the sub-unit composition and small differences in the borders, may lead to exposure of novel immuno-dominant antibody epitopes that lead to non-functional antibodies, and furthermore influence the folding, stability and yield of expression. Candidate antigens from the pre-clinical development expressed in High-Five insect cells using the baculovirus expression vector system were transitioned into the Drosophila Schneider-2 cell (S2 expression-system compliant with clinical development. The functional capacity of antibodies against antigens expressed in High-Five cells or in S2 cells was equivalent. This enabled an extensive down-selection of S2 insect cell-expressed antigens primarily encompassing the minimal CSA-binding region of VAR2CSA. In general, we found differential potency of inhibitory antibodies against antigens with the same borders but of different var2csa sequences. Likewise, we found that subtle size differences in antigens of the same sequence gave varying levels of inhibitory antibodies. The study shows that induction of a functional response against recombinant subunits of the VAR2CSA antigen is unpredictable, demonstrating the need for large-scale screening in order to identify antigens
Vuchelen, Anneleen; Pardon, Els; Steyaert, Jan; Gamain, Benoît; Loris, Remy; Nuland, Nico A. J. van; Ramboarina, Stéphanie
Two nanobodies generated against the VAR2CSA DBL6∊-FCR3 domain involved in pregnancy-associated malaria were selected, expressed, purified and crystallized. The VAR2CSA protein has been closely associated with pregnancy-associated malaria and is recognized as the main adhesin exposed on the surface of Plasmodium falciparum-infected erythrocytes. Chondroitin sulfate A was identified as the main host receptor in the placenta. Single-domain heavy-chain camelid antibodies, more commonly called nanobodies, were selected and produced against the DBL6∊-FCR3 domain of VAR2CSA. Crystals of two specific nanobodies, Nb2907 and Nb2919, identified as strong binders to DBL6∊-FCR3 and the full-length VAR2CSA exposed on the surface of FCR3 P. falciparum-infected erythrocytes, were obtained. Crystals of Nb2907 diffract to 2.45 Å resolution and belong to space group C2 with unit-cell parameters a = 136.1, b = 78.5, c = 103.4 Å, β = 118.8°, whereas Nb2919 crystals diffract to 2.15 Å resolution and belong to space group P4 3 2 1 2 with unit-cell parameters a = b = 62.7, c = 167.2 Å
Tutterrow, Yeung L.; Avril, Marion; Singh, Kavita; Long, Carole A.; Leke, Robert J.; Sama, Grace; Salanti, Ali; Smith, Joseph D.; Leke, Rose G. F.
Placental malaria, caused by sequestration of Plasmodium falciparum-infected erythrocytes in the placenta, is associated with increased risk of maternal morbidity and poor birth outcomes. The parasite antigen VAR2CSA (variant surface antigen 2-chondroitin sulfate A) is expressed on infected erythrocytes and mediates binding to chondroitin sulfate A, initiating inflammation and disrupting homeostasis at the maternal-fetal interface. Although antibodies can prevent sequestration, it is unclear whether parasite clearance is due to antibodies to a single Duffy binding-like (DBL) domain or to an extensive repertoire of antibodies to multiple DBL domains and allelic variants. Accordingly, plasma samples collected longitudinally from pregnant women were screened for naturally acquired antibodies against an extensive panel of VAR2CSA proteins, including 2 to 3 allelic variants for each of 5 different DBL domains. Analyses were performed on plasma samples collected from 3 to 9 months of pregnancy from women living in areas in Cameroon with high and low malaria transmission. The results demonstrate that high antibody levels to multiple VAR2CSA domains, rather than a single domain, were associated with the absence of placental malaria when antibodies were present from early in the second trimester until term. Absence of placental malaria was associated with increasing antibody breadth to different DBL domains and allelic variants in multigravid women. Furthermore, the antibody responses of women in the lower-transmission site had both lower magnitude and lesser breadth than those in the high-transmission site. These data suggest that immunity to placental malaria results from high antibody levels to multiple VAR2CSA domains and allelic variants and that antibody breadth is influenced by malaria transmission intensity. PMID:22331427
Salanti, Ali; Dahlbäck, Madeleine; Turner, Louise
In Plasmodium falciparum-endemic areas, pregnancy-associated malaria (PAM) is an important health problem. The condition is precipitated by accumulation of parasite-infected erythrocytes (IEs) in the placenta, and this process is mediated by parasite-encoded variant surface antigens (VSA) binding...... to chondroitin sulfate A (CSA). Parasites causing PAM express unique VSA types, VSAPAM, which can be serologically classified as sex specific and parity dependent. It is sex specific because men from malaria-endemic areas do not develop VSAPAM antibodies; it is parity dependent because women acquire anti...
Hviid, L; Salanti, A
People living in areas with stable transmission of P. falciparum parasites acquire protective immunity to malaria over a number of years and following multiple disease episodes. Immunity acquired this way is mediated by IgG with specificity for parasite-encoded, clonally variant surface antigens...... that the selective placental accumulation of IEs that characterizes pregnancy-associated malaria (PAM) is caused by an immunologically and functionally unique subset of VSA (VSAPAM) that is only expressed by parasites infecting pregnant women, and that protective immunity to PAM is mediated by IgG with specificity...
Tutterrow, Yeung L; Avril, Marion; Singh, Kavita
erythrocytes and mediates binding to chondroitin sulfate A, initiating inflammation and disrupting homeostasis at the maternal-fetal interface. Although antibodies can prevent sequestration, it is unclear whether parasite clearance is due to antibodies to a single Duffy binding-like (DBL) domain...... or to an extensive repertoire of antibodies to multiple DBL domains and allelic variants. Accordingly, plasma samples collected longitudinally from pregnant women were screened for naturally acquired antibodies against an extensive panel of VAR2CSA proteins, including 2 to 3 allelic variants for each of 5 different...... DBL domains. Analyses were performed on plasma samples collected from 3 to 9 months of pregnancy from women living in areas in Cameroon with high and low malaria transmission. The results demonstrate that high antibody levels to multiple VAR2CSA domains, rather than a single domain, were associated...
Elizabeth G. Kane
Full Text Available Pregnancy-associated malaria, a manifestation of severe malaria, is the cause of up to 200,000 infant deaths a year, through the effects of placental insufficiency leading to growth restriction and preterm delivery. Development of a vaccine is one strategy for control. Plasmodium falciparum-infected red blood cells accumulate in the placenta through specific binding of pregnancy-associated parasite variants that express the VAR2CSA antigen to chondroitin sulphate A on the surface of syncytiotrophoblast cells. Parasite accumulation, accompanied by an inflammatory infiltrate, disrupts the cytokine balance of pregnancy with the potential to cause placental damage and compromise foetal growth. Multigravid women develop immunity towards VAR2CSA-expressing parasites in a gravidity-dependent manner which prevents unfavourable pregnancy outcomes. Although current vaccine design, targeting VAR2CSA antigens, has succeeded in inducing antibodies artificially, this candidate may not provide protection during the first trimester and may only protect those women living in areas endemic for malaria. It is concluded that while insufficient information about placental-parasite interactions is presently available to produce an effective vaccine, incremental progress is being made towards achieving this goal.
Gbédandé, Komi; Cottrell, Gilles; Vianou, Bertin
BACKGROUND: Current knowledge of human immunological responses to pregnancy-associated malaria-specific Plasmodium falciparum protein VAR2CSA concerns almost exclusively B cell-driven antibody-mediated activity. Knowledge of VAR2CSA-specific T cell-mediated activity is minimal by comparison, with...
Babakhanyan, Anna; Leke, Rose G. F.; Salanti, Ali; Bobbili, Naveen; Gwanmesia, Philomina; Leke, Robert J. I.; Quakyi, Isabella A.; Chen, John J.; Taylor, Diane Wallace
In pregnant women, Plasmodium falciparum-infected erythrocytes expressing the VAR2CSA antigen bind to chondroitin sulfate A in the placenta causing placental malaria. The binding site of VAR2CSA is present in the ID1-ID2a region. This study sought to determine if pregnant Cameroonian women naturally acquire antibodies to ID1-ID2a and if antibodies to ID1-ID2a correlate with absence of placental malaria at delivery. Antibody levels to full-length VAR2CSA and ID1-ID2a were measured in plasma samples from 745 pregnant Cameroonian women, 144 Cameroonian men, and 66 US subjects. IgM levels and IgG avidity to ID1-ID2a were also determined. As expected, antibodies to ID1-ID2a were absent in US controls. Although pregnant Cameroonian women developed increasing levels of antibodies to full-length VAR2CSA during pregnancy, no increase in either IgM or IgG to ID1-ID2a was observed. Surprisingly, no differences in antibody levels to ID1-ID2a were detected between Cameroonian men and pregnant women. For example, in rural settings only 8–9% of males had antibodies to full-length VAR2CSA, but 90–96% had antibodies to ID1-ID2a. In addition, no significant difference in the avidity of IgG to ID1-ID2a was found between pregnant women and Cameroonian men, and no correlation between antibody levels at delivery and absence of placental malaria was found. Thus, the response to ID1-ID2a was not pregnancy specific, but predominantly against cross-reactivity epitopes, which may have been induced by other PfEMP1 antigens, malarial antigens, or microbes. Currently, ID1-ID2a is a leading vaccine candidate, since it binds to the CSA with the same affinity as the full-length molecule and elicits binding-inhibitory antibodies in animals. Further studies are needed to determine if the presence of naturally acquired cross-reactive antibodies in women living in malaria endemic countries will alter the response to ID1-ID2a following vaccination with ID1-ID2a. PMID:24505415
Full Text Available In pregnant women, Plasmodium falciparum-infected erythrocytes expressing the VAR2CSA antigen bind to chondroitin sulfate A in the placenta causing placental malaria. The binding site of VAR2CSA is present in the ID1-ID2a region. This study sought to determine if pregnant Cameroonian women naturally acquire antibodies to ID1-ID2a and if antibodies to ID1-ID2a correlate with absence of placental malaria at delivery. Antibody levels to full-length VAR2CSA and ID1-ID2a were measured in plasma samples from 745 pregnant Cameroonian women, 144 Cameroonian men, and 66 US subjects. IgM levels and IgG avidity to ID1-ID2a were also determined. As expected, antibodies to ID1-ID2a were absent in US controls. Although pregnant Cameroonian women developed increasing levels of antibodies to full-length VAR2CSA during pregnancy, no increase in either IgM or IgG to ID1-ID2a was observed. Surprisingly, no differences in antibody levels to ID1-ID2a were detected between Cameroonian men and pregnant women. For example, in rural settings only 8-9% of males had antibodies to full-length VAR2CSA, but 90-96% had antibodies to ID1-ID2a. In addition, no significant difference in the avidity of IgG to ID1-ID2a was found between pregnant women and Cameroonian men, and no correlation between antibody levels at delivery and absence of placental malaria was found. Thus, the response to ID1-ID2a was not pregnancy specific, but predominantly against cross-reactivity epitopes, which may have been induced by other PfEMP1 antigens, malarial antigens, or microbes. Currently, ID1-ID2a is a leading vaccine candidate, since it binds to the CSA with the same affinity as the full-length molecule and elicits binding-inhibitory antibodies in animals. Further studies are needed to determine if the presence of naturally acquired cross-reactive antibodies in women living in malaria endemic countries will alter the response to ID1-ID2a following vaccination with ID1-ID2a.
Fried, Michal; Kurtis, Jonathan D; Swihart, Bruce; Morrison, Robert; Pond-Tor, Sunthorn; Barry, Amadou; Sidibe, Youssoufa; Keita, Sekouba; Mahamar, Almahamoudou; Andemel, Naissem; Attaher, Oumar; Dembele, Adama B; Cisse, Kadidia B; Diarra, Bacary S; Kanoute, Moussa B; Narum, David L; Dicko, Alassane; Duffy, Patrick E
Maternal malaria is a tropical scourge associated with poor pregnancy outcomes. Women become resistant to Plasmodium falciparum pregnancy malaria as they acquire antibodies to the variant surface antigen VAR2CSA, a leading vaccine candidate. Because malaria infection may increase VAR2CSA antibody levels and thereby confound analyses of immune protection, gravidity-dependent changes in antibody levels during and after infection, and the effect of VAR2CSA antibodies on pregnancy outcomes were evaluated. Pregnant women enrolled in a longitudinal cohort study of mother-infant pairs in Ouelessebougou, Mali provided plasma samples at enrollment, gestational week 30-32, and delivery. Antibody levels to VAR2CSA domains were measured using a multiplex bead-based assay. Antibody levels to VAR2CSA were higher in multigravidae than primigravidae. Malaria infection was associated with increased antibody levels to VAR2CSA domains. In primigravidae but not in secundigravidae or multigravidae, antibodies levels sharply declined after an infection. A relationship between any VAR2CSA antibody specificity and protection from adverse pregnancy outcomes was not detected. During malaria infection, primigravidae acquire short-lived antibodies. The lack of an association between VAR2CSA domain antibody reactivity and improved pregnancy outcomes suggests that the recombinant proteins may not present native epitopes targeted by protective antibodies.
Doritchamou, Justin; Sabbagh, Audrey; Jespersen, Jakob S
The VAR2CSA protein of Plasmodium falciparum is transported to and expressed on the infected erythrocyte surface where it plays a key role in placental malaria (PM). It is the current leading candidate for a vaccine to prevent PM. However, the antigenic polymorphism integral to VAR2CSA poses...... a challenge for vaccine development. Based on detailed analysis of polymorphisms in the sequence of its ligand-binding N-terminal region, currently the main focus for vaccine development, we assessed var2csa from parasite isolates infecting pregnant women. The results reveal for the first time the presence...
Nielsen, Morten A; Pinto, Vera V; Resende, Mafalda
between a parasite protein expressed on erythrocytes named variant surface antigen 2-chondroitin sulfate A (VAR2CSA) and CSA on syncytiotrophoblasts. VAR2CSA is a large polymorphic protein consisting of six Duffy binding-like (DBL), domains and with current constraints on recombinant protein production...... which induce antibodies that inhibit CSA binding of different parasite strains. In this study, we produced a large panel of VAR2CSA proteins and raised antibodies against these antigens. We show that antibodies against the DBL4 domain effectively inhibit parasite binding. As the inhibition...... was not limited to homologous parasite strains, it seems feasible to base a protective malaria vaccine on a single VAR2CSA DBL domain....
Salanti, Ali; Lavstsen, Thomas; Nielsen, Morten A.; Theander, Thor G.; Leke, Rose G. F.; Lo, Yeung Y.; Bobbili, Naveen; Arnot, David E.; Taylor, Diane W.
Placental malaria infections are caused by Plasmodium falciparum–infected red blood cells sequestering in the placenta by binding to chondroitin sulfate A, mediated by VAR2CSA, a variant of the PfEMP1 family of adhesion antigens. Recent studies have shown that many P. falciparum genomes have multiple genes coding for different VAR2CSA proteins, and parasites with >1 var2csa gene appear to be more common in pregnant women with placental malaria than in nonpregnant individuals. We present evidence that, in pregnant women, parasites containing multiple var2csa-type genes possess a selective advantage over parasites with a single var2csa gene. Accumulation of parasites with multiple copies of the var2csa gene during the course of pregnancy was also correlated with the development of antibodies involved in blocking VAR2CSA adhesion. The data suggest that multiplicity of var2csa-type genes enables P. falciparum parasites to persist for a longer period of time during placental infections, probably because of their greater capacity for antigenic variation and evasion of variant-specific immune responses. PMID:21592998
Amulic, Borko; Salanti, Ali; Lavstsen, Thomas
contains a small upstream open reading frame that acts to repress translation of the resulting mRNA, revealing a novel form of gene regulation in malaria parasites. The mechanism underlying this translational repression is reversible, allowing high levels of protein translation upon selection, thus...
Sisse B Ditlev
Full Text Available Placental malaria is a major health problem for both pregnant women and their fetuses in malaria endemic regions. It is triggered by the accumulation of Plasmodium falciparum-infected erythrocytes (IE in the intervillous spaces of the placenta and is associated with foetal growth restriction and maternal anemia. IE accumulation is supported by the binding of the parasite-expressed protein VAR2CSA to placental chondroitin sulfate A (CSA. Defining specific CSA-binding epitopes of VAR2CSA, against which to target the immune response, is essential for the development of a vaccine aimed at blocking IE adhesion. However, the development of a VAR2CSA adhesion-blocking vaccine remains challenging due to (i the large size of VAR2CSA and (ii the extensive immune selection for polymorphisms and thereby non-neutralizing B-cell epitopes. Camelid heavy-chain-only antibodies (HcAbs are known to target epitopes that are less immunogenic to classical IgG and, due to their small size and protruding antigen-binding loop, able to reach and recognize cryptic, conformational epitopes which are inaccessible to conventional antibodies. The variable heavy chain (VHH domain is the antigen-binding site of camelid HcAbs, the so called Nanobody, which represents the smallest known (15 kDa intact, native antigen-binding fragment. In this study, we have used the Nanobody technology, an approach new to malaria research, to generate small and functional antibody fragments recognizing unique epitopes broadly distributed on VAR2CSA.
Nunes-Silva, Sofia; Gangnard, Stéphane; Vidal, Marta; Vuchelen, Anneleen; Dechavanne, Sebastien; Chan, Sherwin; Pardon, Els; Steyaert, Jan; Ramboarina, Stephanie; Chêne, Arnaud; Gamain, Benoît
VAR2CSA stands today as the leading vaccine candidate aiming to protect future pregnant women living in malaria endemic areas against the severe clinical outcomes of pregnancy associated malaria (PAM). The rational design of an efficient VAR2CSA-based vaccine relies on a profound understanding of the molecular interactions associated with P. falciparum infected erythrocyte sequestration in the placenta. Following immunization of a llama with the full-length VAR2CSA recombinant protein, we have expressed and characterized a panel of 19 nanobodies able to recognize the recombinant VAR2CSA as well as the surface of erythrocytes infected with parasites originating from different parts of the world. Domain mapping revealed that a large majority of nanobodies targeted DBL1X whereas a few of them were directed towards DBL4ε, DBL5ε and DBL6ε. One nanobody targeting the DBL1X was able to recognize the native VAR2CSA protein of the three parasite lines tested. Furthermore, four nanobodies targeting DBL1X reproducibly inhibited CSA adhesion of erythrocytes infected with the homologous NF54-CSA parasite strain, providing evidences that DBL1X domain is part or close to the CSA binding site. These nanobodies could serve as useful tools to identify conserved epitopes shared between different variants and to characterize the interactions between VAR2CSA and CSA.
Gnidehou, Sedami; Jessen, Leon Ivar; Gangnard, Stephane
on the surface of placental parasites. Despite high DBL5e sequence homology among parasite isolates, sequence analyses identified motifs in DBL5e that discriminate parasites according to donor's parity. Moreover, recombinant proteins of two VAR2CSA DBL5e variants displayed diverse recognition patterns by plasma...... from malaria-exposed women, and diverse proteoglycan binding abilities. Conclusions/Significance: This study provides insights into conserved and exposed B cell epitopes in DBL5e that might be a focus for cross reactivity. The importance of sequence variation in VAR2CSA as a critical challenge...
Dahlbäck, Madeleine; Jørgensen, Lars M; Nielsen, Morten A
Malaria during pregnancy is a major health problem for African women. The disease is caused by Plasmodium falciparum malaria parasites, which accumulate in the placenta by adhering to chondroitin sulfate A (CSA). The interaction between infected erythrocytes and the placental receptor is mediated...
Babakhanyan, Anna; Tutterrow, Yeung L; Bobbili, Naveen
Intermittent preventive treatment (IPT) and insecticide-treated bed nets are the standard of care for preventing malaria in pregnant women. Since these preventive measures reduce exposure to malaria, their influence on the antibody (Ab) response to the parasite antigen VAR2CSA was evaluated...... in pregnant Cameroonian women exposed to holoendemic malaria. Ab levels to full-length VAR2CSA (FV2), variants of the six Duffy binding like (DBL) domains, and proportion of high avidity Ab to FV2 were measured longitudinally in 92 women before and 147 women after IPT. As predicted, reduced exposure...
Nielsen, Morten A; Resende, Mafalda; Alifrangis, Michael
In areas of high Plasmodium falciparum transmission, immunity to malaria is acquired during childhood, so that adults in general are clinically immune. One exception is that first-time pregnant women are susceptible to pregnancy-associated malaria caused by accumulation of parasites in the placen...
Salanti, Ali; Resende, Mafalda; Ditlev, Sisse B
. In this study, it is demonstrated that other domains of VAR2CSA also can induce antibodies with inhibitory activity. METHODS: All VAR2CSA domains from the 3D7 and HB3 parasites were produced in Baculovirus-transfected insect cells. Groups of three rats per protein were immunized and anti-sera were tested...
Sander, Adam F; Salanti, Ali; Lavstsen, Thomas
in the VAR2CSA protein, sequence variation in the DBL2X region of var2csa genes in 54 P.falciparum samples was analyzed. Chromosome mapping of var2csa loci was carried out and a quantitative PCR assay was developed to estimate the number of var2csa genes in P.falciparum isolates from the placenta of pregnant....... falciparum isolates. One gene is on chromosome 12 but additional var2csa-type genes are on different chromosomes in different isolates. Multiplicity of var2csa genes appears more common in infected placentae than in samples from non-pregnant donors indicating a possible advantage of this genotype...
Tuikue Ndam, N G; Salanti, A; Le-Hesran, J-Y
demonstrated that a single P. falciparum infection was able to trigger a VAR2CSA-specific antibody response. Among women with infected placentas, women with high anti-VAR2CSA IgG levels at enrollment were more likely to present with a past infection than with an acute/chronic infection. CONCLUSIONS: Anti-VAR2...... (VSAPAM). Several studies have shown that 1 var gene, var2csa, is transcribed at high levels and expressed in CSA-binding Plasmodium falciparum parasites. METHODS: Plasma levels of anti-VAR2CSA immunoglobulin G (IgG) in Senegalese women were measured during pregnancy by enzyme-linked immunosorbent assay......, using 3 recombinant proteins representing 3 domains of the var2csa gene product. RESULTS: The 3 recombinant proteins were specifically recognized by plasma from pregnant women but not by control plasma. A parity-dependent recognition pattern was observed with 2 of the 3 VAR2CSA antigens. A kinetic study...
Nielsen, Morten A; dos Santos Marques Resende, Mafalda; de Jongh, Willem A
-functional antibodies, and furthermore influence the folding, stability and yield of expression. Candidate antigens from the pre-clinical development expressed in High-Five insect cells using the baculovirus expression vector system were transitioned into the Drosophila Schneider-2 cell (S2) expression-system compliant...... with clinical development. The functional capacity of antibodies against antigens expressed in High-Five cells or in S2 cells was equivalent. This enabled an extensive down-selection of S2 insect cell-expressed antigens primarily encompassing the minimal CSA-binding region of VAR2CSA. In general, we found...
Ditlev, Sisse B; Nielsen, Morten A; Resende, Mafalda
and is the leading candidate for a placental malaria vaccine. Antibodies induced in rats against the recombinant DBL4e domain of VAR2CSA inhibit the binding of a number of laboratory and field parasite isolates to CSA. In this study, we used a DBL4e peptide-array to identify epitopes targeted by DBL4e...... might be involved in the induction of inhibitory antibodies induced by the recombinant DBL4e domain....
Fodjo, Barriere A Y; Atemnkeng, Njika; Esemu, Livo
villages and 160 children with severe malaria from the city. Results: Low Ab levels to VAR2CSA were detected in children; however, Ab levels to FV2 in teenagers were rare. Children preferentially recognized DBL2 (56-70%) and DBL4 (50-60%), while multigravidae produced high levels of IgG to DBL3, DBL5...... and FV2. Sixty-seven percent of teenage girls (n = 16/24) recognized ID1-ID2a region of VAR2CSA. Children with severe forms of malaria had significantly higher IgG to merozoite antigens (all p 0.05) when compared to the healthy children. Conclusion: The study...... suggests that children, including teenage girls acquire Ab to VAR2CSA domains and FV2, but Ab levels are much lower than those needed to protect women from placental infections and repertoire of Ab responses to DBL domains is different from those in pregnant women. Interestingly, children with severe...
Magistrado, Pamela A; Minja, Daniel; Doritchamou, Justin
Malaria during pregnancy is a major cause of intra-uterine growth-retardation and infant death in sub-Saharan Africa. Ideally, this could be prevented by a vaccine delivered before the first pregnancy. Antibodies against domain DBL4¿ from VAR2CSA has been shown to inhibit adhesion of laboratory i...
Bigey, Pascal; Gnidehou, Sédami; Doritchamou, Justin
Background. Binding to chondroitin sulfate A by VAR2CSA, a parasite protein expressed on infected erythrocytes, allows placental sequestration of Plasmodium falciparum-infected erythrocytes. This leads to severe consequences such as maternal anemia, stillbirths, and intrauterine growth retardation....... The latter has been clearly associated to increased morbidity and mortality of the infants. Acquired anti-VAR2CSA antibodies have been associated with improved pregnancy outcomes, suggesting a vaccine could prevent the syndrome. However, identifying functionally important regions in the large VAR2CSA protein...
Agerbæk, Mette Ø.; Pereira, Marina A.; Clausen, Thomas M.; Pehrson, Caroline; Oo, Htoo Zarni; Spliid, Charlotte; Rich, Jamie R.; Fung, Vincent; Nkrumah, Francis; Neequaye, Janet; Biggar, Robert J.; Reynolds, Steven J.; Tosato, Giovanna; Pullarkat, Sheeja T.; Ayers, Leona W.; Theander, Thor G.; Daugaard, Mads; Bhatia, Kishor; Nielsen, Morten A.; Mbulaiteye, Sam M.; Salanti, Ali
Burkitt lymphoma (BL) is a malignant disease, which is frequently found in areas with holoendemic Plasmodium falciparum malaria. We have previously found that the VAR2CSA protein is present on malaria-infected erythrocytes and facilitates a highly specific binding to the placenta. OfCS is absent from other non-malignant tissues and thus VAR2CSA generally facilitates parasite sequestration and accumulation in pregnant women. In this study, we show that the specific receptor for VAR2CSA, the oncofetal chondroitin sulfate (ofCS), is likewise present in BL tissue and cell lines. We therefore explored whether ofCS in BL could act as anchor-site for VAR2CSA-expressing infected erythrocytes. In contrast to the placenta, we found no evidence of in vivo sequestering of infected erythrocytes in the BL tissue. Furthermore, we found VAR2CSA specific antibody titers in children with endemic BL to be lower than in control children from the same malaria endemic region. The abundant presence of ofCS in BL tissue and the absence of ofCS in non-malignant tissue, encouraged us to examine whether recombinant VAR2CSA could be used to target BL. We confirmed the binding of VAR2CSA to BL-derived cells and showed that a VAR2CSA drug conjugate efficiently killed the BL-derived cell lines in vitro. These results identify ofCS as a novel therapeutic BL target and highlight how VAR2CSA could be used as a tool for the discovery of novel approaches for directing BL therapy. PMID:27997697
Agerbaek, Mette Ø; Pereira, Marina A; Clausen, Thomas M; Pehrson, Caroline; Oo, Htoo Zarni; Spliid, Charlotte; Rich, Jamie R; Fung, Vincent; Nkrumah, Francis; Neequaye, Janet; Biggar, Robert J; Reynolds, Steven J; Tosato, Giovanna; Pullarkat, Sheeja T; Ayers, Leona W; Theander, Thor G; Daugaard, Mads; Bhatia, Kishor; Nielsen, Morten A; Mbulaiteye, Sam M; Salanti, Ali
Burkitt lymphoma (BL) is a malignant disease, which is frequently found in areas with holoendemic Plasmodium falciparum malaria. We have previously found that the VAR2CSA protein is present on malaria-infected erythrocytes and facilitates a highly specific binding to the placenta. ofCS is absent in other non-malignant tissues and thus VAR2CSA generally facilitates parasite sequestration and accumulation in pregnant women. In this study, we show that the specific receptor for VAR2CSA, the oncofetal chondroitin sulfate (ofCS), is likewise present in BL tissue and cell lines. We therefore explored whether ofCS in BL could act as anchor site for VAR2CSA-expressing infected erythrocytes. In contrast to the placenta, we found no evidence of in vivo sequestering of infected erythrocytes in the BL tissue. Furthermore, we found VAR2CSA-specific antibody titers in children with endemic BL to be lower than in control children from the same malaria endemic region. The abundant presence of ofCS in BL tissue and the absence of ofCS in non-malignant tissue encouraged us to examine whether recombinant VAR2CSA could be used to target BL. We confirmed the binding of VAR2CSA to BL-derived cells and showed that a VAR2CSA drug conjugate efficiently killed the BL-derived cell lines in vitro. These results identify ofCS as a novel therapeutic BL target and highlight how VAR2CSA could be used as a tool for the discovery of novel approaches for directing BL therapy. © 2016 UICC.
Ditlev, Sisse B; Florea, Raluca; Nielsen, Morten A
adhesion. However, the development of a VAR2CSA adhesion-blocking vaccine remains challenging due to (i) the large size of VAR2CSA and (ii) the extensive immune selection for polymorphisms and thereby non-neutralizing B-cell epitopes. Camelid heavy-chain-only antibodies (HcAbs) are known to target epitopes...... that are less immunogenic to classical IgG and, due to their small size and protruding antigen-binding loop, able to reach and recognize cryptic, conformational epitopes which are inaccessible to conventional antibodies. The variable heavy chain (VHH) domain is the antigen-binding site of camelid HcAbs, the so...
Khunrae, Pongsak; Dahlbäck, Madeleine; Nielsen, Morten A
in the pathogenesis of severe P. falciparum infection. In pregnant women the parasites express a single and unique member of the PfEMP1 family named VAR2CSA, which is associated with the ability of the infected erythrocytes to adhere specifically to chondroitin sulphate A (CSA) in the placenta. Several DBL domains......Plasmodium falciparum malaria remains one of the world's leading causes of human suffering and poverty. Each year, the disease takes 1-3 million lives, mainly in sub-Saharan Africa. The adhesion of parasite-infected erythrocytes to the vascular endothelium or the placenta is the key event...
Tuikue Ndam N.
Full Text Available The consequences of pregnancy-associated malaria on pregnant women (anaemia, their babies (birth weight reduction, and infants (increased morbidity and mortality are well documented. Field observations during the last decade have underlined the key role of the interactions between P. falciparum variable surface antigens expressed on infected erythrocytes and a novel receptor: chondroitin sulfate A (CSA for the placental sequestration of infected erythrocytes. Identification of a distinct P. falciparum erythrocyte membrane protein 1 (PfEMP1 variant, VAR2CSA, as the dominant variant surface antigen and as a clinically important target for protective immune response to pregnancy-associated malaria has raised hope for developing a new preventive strategy based on inducing these immune responses by vaccination. However, despite particular structure and interclonal conservation of VAR2CSA among other PfEMP1, significant challenges still exist concerning the development of a VAR2CSA-based vaccine with profound efficacy.
Barfod, Lea; Nielsen, Morten A; Turner, Louise
We raised specific antisera against recombinant VAR2CSA domains produced in Escherichia coli and in insect cells. All were reactive in enzyme-linked immunosorbent assay, but only insect cell-derived constructs induced immunoglobulin G (IgG) that was reactive with native VAR2CSA on the surface...
Chemistry (App I) . VAR2CSA binds specifically to CSA in the placental tissue of pregnant women hereby causing severe malaria symptoms endangering both mother and child. The minimal VAR2CSA region required to effectively bind CSA was determined to be the N-terminal DBL domain, DBL2X which we locate......Infection with the pathogenic Plasmodium falciparum parasite causes the potentially deadly Malaria disease which leads to over 1 million fatalities each year according to the WHO (World Health Organization). Individuals subjected to multiple infections gradually become immune to the disease...... symptoms and vaccine research is focused on trying to mimic or advance this immune acquisition. Immunity is primarily caused by acquisition of antibodies directed against a family of Plasmodium protein antigens called PfEMP1s located on the surface of infected erythrocytes. The PfEMP1 proteins are adhesive...
Fried, Michal; Hixson, Kim K.; Anderson, Lori; Ogata, Yuko; Mutabingwa, Theonest K.; Duffy, Patrick E.
Malaria proteins expressed on the surface of Plasmodium falciparum infected erythrocytes (IE) mediate adhesion and are targeted by protective immune responses. During pregnancy, IE sequester in the placenta. Placental IE bind to the molecule chondroitin sulfate A (CSA) and preferentially transcribe the gene that encodes VAR2CSA, a member of the PfEMP1 variant surface antigen family. Over successive pregnancies women develop specific immunity to CSA-binding IE and antibodies to VAR2CSA. We used tandem mass spectrometry together with accurate mass and time tag technology to study IE membrane fractions of placental parasites. VAR2CSA peptides were detected in placental IE and in IE from children, but the MC variant of VAR2CSA was specifically associated with placental IE. We identified six conserved hypothetical proteins with putative TM or signal peptides that were exclusively expressed by the placental IE, and 11 such proteins that were significantly more abundant in placental IE. One of these hypothetical proteins, PFI1785w, is a 42kDa molecule detected by Western blot in parasites infecting pregnant women but not those infecting children.
Background: Vaccine antigens targeting specific P. falciparum parasite stages are under pre-clinical ... against individual antigen components in a dual stage anti-malaria vaccine. ..... (D8428, Sigma Aldrich) was prepared in Dulbecco's PBS.
Resende, Mafalda; Nielsen, Morten A.; Dahlbaeck, Madeleine
Background: Pregnancy malaria is caused by Plasmodium falciparum-infected erythrocytes binding the placental receptor chondroitin sulfate A (CSA). This results in accumulation of parasites in the placenta with severe clinical consequences for the mother and her unborn child. Women become resistan...
Matondo, Sungwa; Thrane, Susan; Janitzek, Christoph Mikkel
Catcher peptide. The covalent interaction between SpyTag/SpyCatcher enables the formation of DBL1x-DBL2x-ID2a:CSP conjugate vaccine. Immunogenicity and quality of antibody responses induced by the conjugate vaccine, as well as a control CSP-SpyCatcher vaccine, was tested in BALB/c mice. Results: Serum samples...... obtained from mice immunized with the conjugate vaccine were able to recognize both untagged DBL1x-DBL2x-ID2a as well as CSP antigen. Moreover, the geometric mean anti-CSP antibody titer was 1.9-fold higher in serum (at day 35 and 55 post-first immunization) from mice immunized with the conjugate vaccine......, as compared to mice receiving the control vaccine. Conclusion: The data obtained in this study serves as proof-of-concept for the simultaneous induction of antibodies directed against individual antigen components in a dual stage anti-malaria vaccine....
Pehrson, Caroline; Heno, Kristine Klysner; Adams, Yvonne
BACKGROUND: Malaria in pregnancy is associated with significant morbidity in pregnant women and their offspring. Plasmodium falciparum infected erythrocytes (IE) express VAR2CSA that mediates binding to chondroitin sulphate A (CSA) in the placenta. Two VAR2CSA-based vaccines for placental malaria...
Salanti, Ali; Clausen, Thomas M.; Agerbæk, Mette Ø.
Plasmodium falciparum engineer infected erythrocytes to present the malarial protein, VAR2CSA, which binds a distinct type chondroitin sulfate (CS) exclusively expressed in the placenta. Here, we show that the same CS modification is present on a high proportion of malignant cells and that it can...
Magistrado, Pamela; Salanti, Ali; Tuikue Ndam, Nicaise G
Malaria remains a major threat, in sub-Saharan Africa primarily, and the most deadly infections are those with Plasmodium falciparum. Pregnancy-associated malaria is a clinically important complication of infection; it results from a unique interaction between proteoglycans in the placental inter...
Dahlback, Madeleine; Rask, Thomas Salhøj; Andersen, Pernille
Pregnancy-associated malaria is a major health problem, which mainly affects primigravidae living in malaria endemic areas. The syndrome is precipitated by accumulation of infected erythrocytes in placental tissue through an interaction between chondroitin sulphate A on syncytiotrophoblasts and a...
Ndam, Nicaise Tuikue; Denoeud-Ndam, Lise; Doritchamou, Justin
Placental malaria is caused by Plasmodium falciparum-infected erythrocytes that bind to placental tissue. Binding is mediated by VAR2CSA, a parasite antigen coded by the var gene, which interacts with chondroitin sulfate A (CSA). Consequences include maternal anemia and fetal growth retardation....... Antibody-mediated immunity to placental malaria is acquired during successive pregnancies, but the target of VAR2CSA-specific protective antibodies is unclear. We assessed VAR2CSA-specific antibodies in pregnant women and analyzed their relationships with protection against placental infection, preterm...... birth, and low birthweight. Antibody responses to the N-terminal region of VAR2CSA during early pregnancy were associated with reduced risks for infections and low birthweight. Among women infected during pregnancy, an increase in CSA binding inhibition was associated with reduced risks for placental...
Goel, Suchi; Valiyaveettil, Manojkumar; Achur, Rajeshwara N
adherence. However, how CLAG9 influences this process remains unknown. In this study, we show that CLAG9 interacts with VAR2CSA, a PfEMP1 that mediates IRBC adherence to chondroitin 4-sulfate in the placenta. Importantly, our results show that the adherent parasites synthesize CLAG9 at two stages--the early......Plasmodium falciparum erythrocyte membrane protein 1 (PfEMP1) family members mediate the adherence of parasite-infected red blood cells (IRBCs) to various host receptors. A previous study has shown that the parasite protein, cytoadherence-linked asexual gene 9 (CLAG9), is also essential for IRBC...... within the parasite. Based on these findings, we propose that CLAG9 plays a critical role in the trafficking of PfEMP1s onto the IRBC surface. These results have important implications for the development of therapeutics for cerebral, placental, and other cytoadherence-associated malaria illnesses....
Fried, Michal; Avril, Marion; Chaturvedi, Richa
a vaccine targeting individual Duffy binding-like (DBL) domains. In this study, a consortium of laboratories under the Pregnancy Malaria Initiative compared the functional activity of antiadhesion antibodies elicited by different VAR2CSA domains and variants produced in prokaryotic and eukaryotic expression...... systems. Antisera were initially tested against laboratory lines of maternal parasites, and the most promising reagents were evaluated in the field against fresh placental parasite samples. Recombinant proteins expressed in Escherichia coli elicited antibody levels similar to those expressed in eukaryotic...
Resende, Mafalda; Ditlev, Sisse B; Nielsen, Morten A
Individuals living in areas with high Plasmodium falciparum transmission acquire immunity to malaria over time and adults have a markedly reduced risk of contracting severe disease. However, pregnant women constitute an important exception. Pregnancy-associated malaria is a major cause of mother....... In this study, we confirm the CSA-binding of these DBL domains, however, the analysis of a number of DBL domains of a non-VAR2CSA origin shows that CSA-binding is not exclusively restricted to VAR2CSA DBL domains. Furthermore, we show that the VAR2CSA DBL domains as well as other DBL domains also bind heparan...
Soerli, J; Barfod, L; Lavstsen, T
Pregnancy-associated Plasmodium falciparum malaria (PAM) is a major cause of morbidity and mortality in African women and their offspring. PAM is characterized by accumulation of infected erythrocytes (IEs) that adhere to chondroitin sulphate A (CSA) in the placental intervillous space. We show h...... transcription of var2csa. The results corroborate current efforts to develop PAM-specific vaccines based on VAR2CSA....
Hviid, Lars; Marinho, Claudio R F; Staalsoe, Trine
Pregnant women are at increased malaria risk. The infections are characterized by placental accumulation of infected erythrocytes (IEs) with adverse consequences for mother and baby. Placental IE sequestration in the intervillous space is mediated by variant surface antigens (VSAs) selectively...... expressed in placental malaria (PM) and specific for chondroitin sulfate A (CSA). In Plasmodium falciparum, these VSA(PM) appear largely synonymous with the P. falciparum erythrocyte membrane protein 1 (PfEMP1) family variant VAR2CSA. As rodent malaria parasites do not possess PfEMP1 homologs......, the usefulness of experimental mouse PM models remains controversial. However, many features of murine and human PM are similar, including involvement of VSAs analogous to PfEMP1. It thus appears that rodent model studies can further the understanding of VSA-dependent malaria pathogenesis and immunity....
Nielsen, Morten A; Salanti, Ali
The particular virulence of Plasmodium falciparum manifests in diverse severe malaria syndromes as cerebral malaria, severe anemia and placental malaria. The cause of both the severity and the diversity of infection outcome, is the ability of the infected erythrocyte (IE) to bind a range......-throughput assay used in the preclinical and clinical development of a VAR2CSA based vaccine against placental malaria....
Pinto, V V; Salanti, A; Joergensen, L M
720, Alhydrogel(®) and CAF01. Antibodies induced against DBL4¿-ID4 in combination with these adjuvants inhibited parasite binding to CSA from 82% to 99%. Although, different epitope recognition patterns were obtained for the different formulations, all adjuvant combinations induced strong Th1 and Th2......¿-ID4 to induce binding-inhibitory antibodies when formulated with adjuvants approved for human use. We have characterized the immune response of DBL4¿-ID4 in combination with Freund's complete and incomplete adjuvant and with three adjuvants currently being used in clinical trials: Montanide(®) ISA...... type responses, resulting in IgG with similar binding strength, with to the DBL4¿-ID4 antigen. These results demonstrate that the DBL4¿-ID4 antigen is highly immunogenic and that binding inhibitory antibodies are induced when formulated with any of the tested adjuvants....
Gavina, Kenneth; Gnidehou, Sedami; Arango, Eliana
Malaria in pregnancy can cause serious adverse outcomes for the mother and the fetus. However, little is known about the effects of submicroscopic infections (SMIs) in pregnancy, particularly in areas wherePlasmodium falciparumandPlasmodium vivaxcocirculate. A cohort of 187 pregnant women living ...
Ampomah, Paulina; Stevenson, Liz; Ofori, Michael F
. In this first, to our knowledge, longitudinal study of its kind, we measured B cell subset composition, as well as PfEMP1-specific Ab levels and memory B cell frequencies, in Ghanaian women followed from early pregnancy up to 1 y after delivery. Cell phenotypes and Ag-specific B cell function were assessed...... three times during and after pregnancy. Levels of IgG specific for pregnancy-restricted, VAR2CSA-type PfEMP1 increased markedly during pregnancy and declined after delivery, whereas IgG levels specific for two PfEMP1 proteins not restricted to pregnancy did not. Changes in VAR2CSA-specific memory B cell...
Wang, Christian W; Lavstsen, Thomas; Bengtsson, Dominique C
ABSTRACT: BACKGROUND: Members of the Plasmodium falciparum erythrocyte membrane protein 1 (PfEMP1) adhesion antigen family are major contributors to the pathogenesis of P. falciparum malaria infections. The PfEMP1-encoding var genes are among the most diverse sequences in nature, but three genes......, var1, var2csa and var3 are found conserved in most parasite genomes. The most severe forms of malaria disease are caused by parasites expressing a subset of antigenically conserved PfEMP1 variants. Thus the ubiquitous and conserved VAR3 PfEMP1 is of particular interest to the research field. Evidence...... of VAR3 expression on the infected erythrocyte surface has never been presented, and var3 genes have been proposed to be transcribed and expressed differently from the rest of the var gene family members. METHODS: In this study, parasites expressing VAR3 PfEMP1 were generated using anti-VAR3 antibodies...
Maestre, Amanda; Carmona-Fonseca, Jaime
Women pregnant with their first child are susceptible to severe P. falciparum disease from placental malaria because they lack immunity to placenta-specific cytoadherence proteins. In subsequent pregnancies, as immunity against placental parasites is acquired, there is a reduced risk of adverse effects of malaria on the mother and fetus and asymptomatic parasitaemia is common. In the case of vivax malaria, with increasing reports of severe cases in Asia and South America, the effects of infection by this species during pregnancy remain to be elucidated. This review summarized the main aspects involved in the acquisition of specific antimalarial immune responses during pregnancy with emphasis in research carried out in America and Asia, in order to offer a framework of interpretation for studies on pregnant women with malaria which are recently being produced in these regions. The authors conclude that (1) Effective humoral responses during gestational malaria are mainly directed against variant surface antigens codified by genes of the var2Csa family of P. falciparum; (2) Acquisition of immunity against these variant antigens depends on the degree and intensity of transmission, and the chance increases with age and successive pregnancies; (3) Antibody development is guided by specific cellular immune responses in cases of placental and maternal infection, and (4) The study of the significance of acquisition of specific immunity against both P. falciparum and P. vivax in America, should be performed.
Ampomah, Paulina; Stevenson, Liz; Ofori, Michael F
-linked immunosorbent assay (ELISA) and memory B-cell frequencies by enzyme-linked immunosorbent spot (ELISPOT) assay in a cohort of P. falciparum-exposed nonpregnant Ghanaian women. The antigens used were a VAR2CSA-type PfEMP1 (IT4VAR04) with expression restricted to parasites infecting the placenta, as well as two...... commonly recognized PfEMP1 proteins (HB3VAR06 and IT4VAR60) implicated in rosetting and not pregnancy restricted. This enabled, for the first time, a direct comparison in the same individuals of immune responses specific for a clinically important parasite antigen expressed only during well-defined periods...
Barfod, Lea; Dalgaard, Michael B; Pleman, Suzan T
1 (PfEMP1) family is central to both. Here, we present evidence of a P. falciparum evasion mechanism not previously documented: the masking of PfEMP1-specific IgG epitopes by nonspecific IgM. Nonspecific IgM binding to erythrocytes infected by parasites expressing the PfEMP1 protein VAR2CSA...
Rogerson, Stephen J; Hviid, Lars; Duffy, Patrick E
Understanding of the biological basis for susceptibility to malaria in pregnancy was recently advanced by the discovery that erythrocytes infected with Plasmodium falciparum accumulate in the placenta through adhesion to molecules such as chondroitin sulphate A. Antibody recognition of placental...... infected erythrocytes is dependent on sex and gravidity, and could protect from malaria complications. Moreover, a conserved parasite gene-var2csa-has been associated with placental malaria, suggesting that its product might be an appropriate vaccine candidate. By contrast, our understanding of placental...... immunopathology and how this contributes to anaemia and low birthweight remains restricted, although inflammatory cytokines produced by T cells, macrophages, and other cells are clearly important. Studies that unravel the role of host response to malaria in pathology and protection in the placenta...
Fisayo, Asaolu Modupe
The plasma concentrations of total protein, albumin, immunoglobulins IgG, IgA and IgM and urinary protein were assayed in 250 pregnant Nigerian women with malaria and compared with 250 healthy pregnant women which served as controls. The mean values of plasma total proteins, albumin, IgG and IgA were significantly lowered (P
Agerbaek, Mette Ø; Bento Ayres Pereira, Marina Maria; Clausen, Thomas M
in other non-malignant tissues and thus VAR2CSA generally facilitates parasite sequestration and accumulation in pregnant women. In this study, we show that the specific receptor for VAR2CSA, the oncofetal chondroitin sulfate (ofCS), is likewise present in BL tissue and cell lines. We therefore explored...
Background: Vaccine antigens targeting specific P. falciparum parasite stages are under pre-clinical and clinical development. It seems plausible that vaccine with multiple specificities will offer higher protection. With this hypothesis, we exploited the Spy- Tag/SpyCatcher conjugation system to make a, post expression, dual ...
Draper, Simon J; Angov, Evelina; Horii, Toshihiro
Plasmodium parasites are the causative agent of human malaria, and the development of a highly effective vaccine against infection, disease and transmission remains a key priority. It is widely established that multiple stages of the parasite's complex lifecycle within the human host and mosquito...... vector are susceptible to vaccine-induced antibodies. The mainstay approach to antibody induction by subunit vaccination has been the delivery of protein antigen formulated in adjuvant. Extensive efforts have been made in this endeavor with respect to malaria vaccine development, especially with regard......, with the prospects for the development of a highly effective multi-component/multi-stage/multi-antigen formulation seeming ever more likely. This review will focus on recent progress in protein vaccine design, development and/or clinical testing for a number of leading malaria antigens from the sporozoite...
Giersing, Birgitte K; Dubovsky, Filip; Saul, Allan; Denamur, Francoise; Minor, Philip; Meade, Bruce
Many licensed vaccines are composed of live, attenuated or inactivated whole-cell microorganisms, or they comprise purified components from whole-cell extracts or culture supernatants. For some diseases, pathology is fairly well understood, and there may be known correlates of protection that provide obvious parameters for assessment of vaccine potency. However, this is not always the case, and some effective vaccines are routinely used even though the mechanisms or correlates of protection are unknown. Some more modern vaccine approaches employ purified recombinant proteins, based on molecules that appear on the surface of the pathogen. This is one of the strategies that has been adopted in the quest to develop a malaria vaccine. Use of these parasite antigens as vaccine candidates is supported by substantial epidemiological data, and some have demonstrated the ability to elicit protective responses in animal models of malaria infection. However, there is as yet no immunological correlate of protection and no functional assays or animal models that have demonstrated the ability to predict efficacy in humans. There is little precedence for the most appropriate and practical method for assessing potency of vaccines based on these recombinant molecules for malaria vaccines. This is likely because the majority of malaria vaccine candidates have only recently entered clinical evaluation. The PATH Malaria Vaccine Initiative (MVI) convened a panel with expertise in potency assay design from industry, governmental institutions, and regulatory bodies to discuss and review the rationale, available methods, and best approaches for assessing the potency of recombinant proteins, specifically for their use as malarial vaccines. The aim of this meeting was to produce a discussion document on the practical potency assessment of recombinant protein malaria vaccines, focusing on early phase potency assay development.
Serum protein profile of Malaria patients through SDS-PAGE method. ... reliable method in the diagnosis of antibodies produced against Plasmodium spps. ... of malaria patients may be undertaken for study to develop possible future vaccine.
Malaria, the greatest pandemia in the world, claims an estimated one million lives each year in Africa alone. While it may still be said that for the most part malaria is found in what is known as the world's poverty belt, cases are now frequently diagnosed in western countries. Due to resistant strains of malaria which have developed because of…
Full Text Available Systemic inflammation and sequestration of parasitized erythrocytes are central processes in the pathophysiology of severe Plasmodium falciparum childhood malaria. However, it is still not understood why some children are more at risks to develop malaria complications than others. To identify human proteins in plasma related to childhood malaria syndromes, multiplex antibody suspension bead arrays were employed. Out of the 1,015 proteins analyzed in plasma from more than 700 children, 41 differed between malaria infected children and community controls, whereas 13 discriminated uncomplicated malaria from severe malaria syndromes. Markers of oxidative stress were found related to severe malaria anemia while markers of endothelial activation, platelet adhesion and muscular damage were identified in relation to children with cerebral malaria. These findings suggest the presence of generalized vascular inflammation, vascular wall modulations, activation of endothelium and unbalanced glucose metabolism in severe malaria. The increased levels of specific muscle proteins in plasma implicate potential muscle damage and microvasculature lesions during the course of cerebral malaria.
... less than the risk of catching this infection. Chloroquine has been the drug of choice for protecting against malaria. But because of resistance, it is now only suggested for use in areas where Plasmodium vivax , P. oval , and ...
... bites you, the parasite can get into your blood. The parasite lays eggs, which develop into more parasites. They ... cells until you get very sick. Because the parasites live in the blood, malaria can also be spread through other ways. ...
... Featured Diseases & Conditions Food Allergy HIV/AIDS Influenza Malaria Respiratory Syncytial Virus (RSV) Tuberculosis Zika Virus Find ... To Volunteer for Vaccine Research Studies Volunteer for Malaria Vaccine Research Volunteer Profiles Q&A: Vaccine Clinical ...
Pehrson, Caroline; Mathiesen, Line; Heno, Kristine K
placental tissue. RESULTS: The ex vivo placental perfusion model was modified to study adhesion of infected erythrocytes binding to CSA, endothelial protein C receptor (EPCR) or a transgenic parasite where P. falciparum erythrocyte membrane protein 1 expression had been shut down. Infected erythrocytes......, such as binding to immunoglobulins. Furthermore, other parasite antigens have been associated with placental malaria. These findings have important implications for placental malaria vaccine design. The objective of this study was to adapt and describe a biologically relevant model of parasite adhesion in intact...... expressing VAR2CSA accumulated in perfused placental tissue whereas the EPCR binding and the transgenic parasite did not. Soluble CSA and antibodies specific against VAR2CSA inhibited binding of infected erythrocytes. CONCLUSION: The ex vivo model provides a novel way of studying receptor-ligand interactions...
children who presented with malaria symptoms at the same clinic and tested positive or ... phagocytes immunity and induce anti-inflammatory immune response ...... treatment gap, Malawi will be ready to submit a validation request for virtual .... Conclusions. Vaccination and quarantine are the important disease preventive.
Malaria, caused by the protozoan parasite Plasmodium falciparum, affects around 225. million people yearly and a huge international effort is directed towards combating this grave threat to world health and economic development. Considerable advances have been made in malaria research triggered by the sequencing of its genome in 2002, followed by several high-throughput studies defining the malaria transcriptome and proteome. A protein-protein interaction (PPI) network seeks to trace the dynamic interactions between proteins, thereby elucidating their local and global functional relationships. Experimentally derived PPI network from high-throughput methods such as yeast two hybrid (Y2H) screens are inherently noisy, but combining these independent datasets by computational methods tends to give a greater accuracy and coverage. This review aims to discuss the computational approaches used till date to construct a malaria protein interaction network and to catalog the functional predictions and biological inferences made from analysis of the PPI network. © 2011 Elsevier Inc.
dividing and are far more noticeable than the small amount of clear cyto- plasm surrounding them (Figs 10.6a & 10.6b). Mature schizonts contain 8...edema Same as P. vivax 16 10 • Topics on The paThology of proTozoan and invasive arThropod diseases Figure 10.38 Transmission electron micrograph of...mesangiopathic glo- merulonephropathy caused by quartan malaria, deposition of immune complexes may be demonstrated by electron or immunofluorescence microscopy
Ray, Sandipan; Renu, Durairaj; Srivastava, Rajneesh; Gollapalli, Kishore; Taur, Santosh; Jhaveri, Tulip; Dhali, Snigdha; Chennareddy, Srinivasarao; Potla, Ankit; Dikshit, Jyoti Bajpai; Srikanth, Rapole; Gogtay, Nithya; Thatte, Urmila; Patankar, Swati; Srivastava, Sanjeeva
This study was conducted to analyze alterations in the human serum proteome as a consequence of infection by malaria parasites Plasmodium falciparum and P. vivax to obtain mechanistic insights about disease pathogenesis, host immune response, and identification of potential protein markers. Serum samples from patients diagnosed with falciparum malaria (FM) (n = 20), vivax malaria (VM) (n = 17) and healthy controls (HC) (n = 20) were investigated using multiple proteomic techniques and results were validated by employing immunoassay-based approaches. Specificity of the identified malaria related serum markers was evaluated by means of analysis of leptospirosis as a febrile control (FC). Compared to HC, 30 and 31 differentially expressed and statistically significant (p<0.05) serum proteins were identified in FM and VM respectively, and almost half (46.2%) of these proteins were commonly modulated due to both of the plasmodial infections. 13 proteins were found to be differentially expressed in FM compared to VM. Functional pathway analysis involving the identified proteins revealed the modulation of different vital physiological pathways, including acute phase response signaling, chemokine and cytokine signaling, complement cascades and blood coagulation in malaria. A panel of identified proteins consists of six candidates; serum amyloid A, hemopexin, apolipoprotein E, haptoglobin, retinol-binding protein and apolipoprotein A-I was used to build statistical sample class prediction models. By employing PLS-DA and other classification methods the clinical phenotypic classes (FM, VM, FC and HC) were predicted with over 95% prediction accuracy. Individual performance of three classifier proteins; haptoglobin, apolipoprotein A-I and retinol-binding protein in diagnosis of malaria was analyzed using receiver operating characteristic (ROC) curves. The discrimination of FM, VM, FC and HC groups on the basis of differentially expressed serum proteins demonstrates
Full Text Available This study was conducted to analyze alterations in the human serum proteome as a consequence of infection by malaria parasites Plasmodium falciparum and P. vivax to obtain mechanistic insights about disease pathogenesis, host immune response, and identification of potential protein markers. Serum samples from patients diagnosed with falciparum malaria (FM (n = 20, vivax malaria (VM (n = 17 and healthy controls (HC (n = 20 were investigated using multiple proteomic techniques and results were validated by employing immunoassay-based approaches. Specificity of the identified malaria related serum markers was evaluated by means of analysis of leptospirosis as a febrile control (FC. Compared to HC, 30 and 31 differentially expressed and statistically significant (p<0.05 serum proteins were identified in FM and VM respectively, and almost half (46.2% of these proteins were commonly modulated due to both of the plasmodial infections. 13 proteins were found to be differentially expressed in FM compared to VM. Functional pathway analysis involving the identified proteins revealed the modulation of different vital physiological pathways, including acute phase response signaling, chemokine and cytokine signaling, complement cascades and blood coagulation in malaria. A panel of identified proteins consists of six candidates; serum amyloid A, hemopexin, apolipoprotein E, haptoglobin, retinol-binding protein and apolipoprotein A-I was used to build statistical sample class prediction models. By employing PLS-DA and other classification methods the clinical phenotypic classes (FM, VM, FC and HC were predicted with over 95% prediction accuracy. Individual performance of three classifier proteins; haptoglobin, apolipoprotein A-I and retinol-binding protein in diagnosis of malaria was analyzed using receiver operating characteristic (ROC curves. The discrimination of FM, VM, FC and HC groups on the basis of differentially expressed serum proteins demonstrates
Malaria morbidity and mortality has remained a major health burden in the developing countries especially in tropical Africa. Thus malaria association in pregnancy and its associated complication remains a major health problem to the expectant mothers. In this study a total of five hundred and fifty (550) blood specimens ...
Lusingu, John P A; Vestergaard, Lasse S; Alifrangis, Michael
BACKGROUND: Several studies conducted in areas of medium or low malaria transmission intensity have found associations between malaria immunity and plasma antibody levels to glutamate rich protein (GLURP). This study was conducted to analyse if a similar relationship could be documented in an area...... of intense malaria transmission. METHODS: A six month longitudinal study was conducted in an area of holoendemic malaria transmission in north-eastern Tanzania, where the incidence of febrile malaria decreased sharply by the age of three years, and anaemia constituted a significant part of the malaria...... disease burden. Plasma antibodies to glutamate rich protein (GLURP) were analysed and related with protection against malaria morbidity in models correcting for the effect of age. RESULTS: The risk of febrile malaria episodes was reduced significantly in children with measurable anti-GLURP IgG1 antibodies...
Turner, Louise; Lavstsen, Thomas; Berger, Sanne S
Sequestration of Plasmodium falciparum-infected erythrocytes in host blood vessels is a key triggering event in the pathogenesis of severe childhood malaria, which is responsible for about one million deaths every year. Sequestration is mediated by specific interactions between members of the P....... falciparum erythrocyte membrane protein 1 (PfEMP1) family and receptors on the endothelial lining. Severe childhood malaria is associated with expression of specific PfEMP1 subtypes containing domain cassettes (DCs) 8 and 13 (ref. 3), but the endothelial receptor for parasites expressing these proteins...
Srisutham, Suttipat; Saralamba, Naowarat; Sriprawat, Kanlaya; Mayxay, Mayfong; Smithuis, Frank; Nosten, Francois; Pukrittayakamee, Sasithon; Day, Nicholas P J; Dondorp, Arjen M; Imwong, Mallika
Genetic diversity of the three important antigenic proteins, namely thrombospondin-related anonymous protein (TRAP), apical membrane antigen 1 (AMA1), and 6-cysteine protein (P48/45), all of which are found in various developmental stages of Plasmodium parasites is crucial for targeted vaccine development. While studies related to the genetic diversity of these proteins are available for Plasmodium falciparum and Plasmodium vivax, barely enough information exists regarding Plasmodium malariae. The present study aims to demonstrate the genetic variations existing among these three genes in P. malariae by analysing their diversity at nucleotide and protein levels. Three surface protein genes were isolated from 45 samples collected in Thailand (N = 33), Myanmar (N = 8), and Lao PDR (N = 4), using conventional polymerase chain reaction (PCR) assay. Then, the PCR products were sequenced and analysed using BioEdit, MEGA6, and DnaSP programs. The average pairwise nucleotide diversities (π) of P. malariae trap, ama1, and p48/45 were 0.00169, 0.00413, and 0.00029, respectively. The haplotype diversities (Hd) of P. malariae trap, ama1, and p48/45 were 0.919, 0.946, and 0.130, respectively. Most of the nucleotide substitutions were non-synonymous, which indicated that the genetic variations of these genes were maintained by positive diversifying selection, thus, suggesting their role as a potential target of protective immune response. Amino acid substitutions of P. malariae TRAP, AMA1, and P48/45 could be categorized to 17, 20, and 2 unique amino-acid variants, respectively. For further vaccine development, carboxyl terminal of P48/45 would be a good candidate according to conserved amino acid at low genetic diversity (π = 0.2-0.3). High mutational diversity was observed in P. malariae trap and ama1 as compared to p48/45 in P. malariae samples isolated from Thailand, Myanmar, and Lao PDR. Taken together, these results suggest that P48/45 might be a good vaccine
Miura, Toyokazu; Takeo, Satoru; Ntege, Edward H; Otsuki, Hitoshi; Sawasaki, Tatsuya; Ishino, Tomoko; Takashima, Eizo; Tsuboi, Takafumi
Malaria merozoite apical organelles; microneme and rhoptry secreted proteins play functional roles during and following invasion of host erythrocytes. Among numerous proteins, the rhoptries discharge high molecular weight proteins known as RhopH complex. Recent reports suggest that the RhopH complex is essential for growth and survival of the malaria parasite within erythrocytes. However, an in-depth understanding of the host-parasite molecular interactions is indispensable. Here we utilized a comprehensive mouse erythrocyte protein library consisting of 443 proteins produced by a wheat germ cell-free system, combined with AlphaScreen technology to identify mouse erythrocyte calmyrin as an interacting molecule of the rodent malaria parasite Plasmodium yoelii RhopH complex (PyRhopH). The PyRhopH interaction was dependent on the calmyrin N-terminus and divalent cation capacity. The finding unveils a recommendable and invaluable usefulness of our comprehensive mouse erythrocyte protein library together with the AlphaScreen technology in investigating a wide-range of host-parasite molecular interactions. Copyright © 2018 Elsevier Inc. All rights reserved.
Fernanda G. Versiani
Full Text Available The human malaria is widely distributed in the Middle East, Asia, the western Pacific, and Central and South America. Plasmodium vivax started to have the attention of many researchers since it is causing diseases to millions of people and several reports of severe malaria cases have been noticed in the last few years. The lack of in vitro cultures for P. vivax represents a major delay in developing a functional malaria vaccine. One of the major candidates to antimalarial vaccine is the merozoite surface protein-1 (MSP1, which is expressed abundantly on the merozoite surface and capable of activating the host protective immunity. Studies have shown that MSP-1 possesses highly immunogenic fragments, capable of generating immune response and protection in natural infection in endemic regions. This paper shows humoral immune response to different proteins of PvMSP1 and the statement of N-terminal to be added to the list of potential candidates for malaria vivax vaccine.
Full Text Available Malaria is a disease caused by parasites of Plasmodium species. It is responsible for around 1-2 million deaths annually, mainly children under the age of 5. It occurs mainly in tropical and subtropical areas.Malaria is caused by five Plasmodium species:[i] P. falciparum, P. malariae, P. vivax, P. knowlesi[/i] and [i]P. ovale[/i]. Mosquitoes spread the disease by biting humans. The malaria parasite has two stages of development: the human stage and the mosquito stage. The first stage occurs in the human body and is divided into two phases: the liver phase and the blood phase.The invasion of erythrocytes by [i]Plasmodium[/i] merozoites is a multistep process of specific protein interactions between the parasite and red blood cell. The first step is the reversible merozoite attachment to the erythrocyte followed by its apical reorientation, then formation of an irreversible “tight” junction and finally entry into the red cell in a parasitophorous vacuole.The blood phase is supported by a number of proteins produced by the parasite. The merozoite surface GPI-anchored proteins (MSP-1, 2, 4, 5, 8 and 10 assist in the process of recognition of susceptible erythrocytes, apical membrane antigen (AMA-1 may be directly responsible for apical reorientation of the merozoite and apical proteins which function in tight junction formation. These ligands are members of two families: Duffy binding-like (DBL and reticulocyte binding-like (RBL proteins. In [i]Plasmodium[/i] [i]falciparum[/i] the DBL family includes: EBA-175, EBA-140 (BAEBL, EBA-181 (JESEBL, EBA-165 (PEBL and EBL-1 ligands.To date, no effective antimalarial vaccine has been developed, but there are several studies for this purpose. Therefore, it is crucial to understand the molecular basis of host cells invasion by parasites. Major efforts are focused on developing a multiantigenic and multiepitope vaccine preventing all steps of [i]Plasmodium[/i] invasion.
Sor-suwan, Sriwatapron; Jariyapan, Narissara; Roytrakul, Sittiruk; Paemanee, Atchara; Phumee, Atchara; Phattanawiboon, Benjarat; Intakhan, Nuchpicha; Chanmol, Wetpisit; Bates, Paul A.; Saeung, Atiporn; Choochote, Wej
Malaria sporozoites must invade the salivary glands of mosquitoes for maturation before transmission to vertebrate hosts. The duration of the sporogonic cycle within the mosquitoes ranges from 10 to 21 days depending on the parasite species and temperature. During blood feeding salivary gland proteins are injected into the vertebrate host, along with malaria sporozoites in the case of an infected mosquito. To identify salivary gland proteins depleted after blood feeding of female Anopheles ca...
Absalon, Sabrina; Robbins, Jonathan A; Dvorin, Jeffrey D
Blood-stage replication of the human malaria parasite Plasmodium falciparum occurs via schizogony, wherein daughter parasites are formed by a specialized cytokinesis known as segmentation. Here we identify a parasite protein, which we name P. falciparum Merozoite Organizing Protein (PfMOP), as essential for cytokinesis of blood-stage parasites. We show that, following PfMOP knockdown, parasites undergo incomplete segmentation resulting in a residual agglomerate of partially divided cells. While organelles develop normally, the structural scaffold of daughter parasites, the inner membrane complex (IMC), fails to form in this agglomerate causing flawed segmentation. In PfMOP-deficient gametocytes, the IMC formation defect causes maturation arrest with aberrant morphology and death. Our results provide insight into the mechanisms of replication and maturation of malaria parasites.
Belmont, Martin; Cazzamali, Giuseppe; Williamson, Michael
The mosquito Anopheles gambiae is an important vector for malaria, which is one of the most serious human parasitic diseases in the world, causing up to 2.7 million deaths yearly. To contribute to our understanding of A. gambiae and to the transmission of malaria, we have now cloned four evolutio......The mosquito Anopheles gambiae is an important vector for malaria, which is one of the most serious human parasitic diseases in the world, causing up to 2.7 million deaths yearly. To contribute to our understanding of A. gambiae and to the transmission of malaria, we have now cloned four...... evolutionarily related G protein-coupled receptors (GPCRs) from this mosquito and expressed them in Chinese hamster ovary cells. After screening of a library of thirty-three insect or other invertebrate neuropeptides and eight biogenic amines, we could identify (de-orphanize) three of these GPCRs as...... relationship to the A. gambiae and other insect AKH receptors suggested that it is a receptor for an AKH-like peptide. This is the first published report on evolutionarily related AKH, corazonin, and CCAP receptors in mosquitoes....
Guimarães, Lilian O; Wunderlich, Gerhard; Alves, João M P; Bueno, Marina G; Röhe, Fabio; Catão-Dias, José L; Neves, Amanda; Malafronte, Rosely S; Curado, Izilda; Domingues, Wilson; Kirchgatter, Karin
The merozoite surface protein 1 (MSP1) gene encodes the major surface antigen of invasive forms of the Plasmodium erythrocytic stages and is considered a candidate vaccine antigen against malaria. Due to its polymorphisms, MSP1 is also useful for strain discrimination and consists of a good genetic marker. Sequence diversity in MSP1 has been analyzed in field isolates of three human parasites: P. falciparum, P. vivax, and P. ovale. However, the extent of variation in another human parasite, P. malariae, remains unknown. This parasite shows widespread, uneven distribution in tropical and subtropical regions throughout South America, Asia, and Africa. Interestingly, it is genetically indistinguishable from P. brasilianum, a parasite known to infect New World monkeys in Central and South America. Specific fragments (1 to 5) covering 60 % of the MSP1 gene (mainly the putatively polymorphic regions), were amplified by PCR in isolates of P. malariae and P. brasilianum from different geographic origin and hosts. Sequencing of the PCR-amplified products or cloned PCR fragments was performed and the sequences were used to construct a phylogenetic tree by the maximum likelihood method. Data were computed to give insights into the evolutionary and phylogenetic relationships of these parasites. Except for fragment 4, sequences from all other fragments consisted of unpublished sequences. The most polymorphic gene region was fragment 2, and in samples where this region lacks polymorphism, all other regions are also identical. The low variability of the P. malariae msp1 sequences of these isolates and the identification of the same haplotype in those collected many years apart at different locations is compatible with a low transmission rate. We also found greater diversity among P. brasilianum isolates compared with P. malariae ones. Lastly, the sequences were segregated according to their geographic origins and hosts, showing a strong genetic and geographic structure. Our data
Siriwardhana, Chathura; Fang, Rui; Salanti, Ali
Background Plasmodium falciparum infections are especially severe in pregnant women because infected erythrocytes (IE) express VAR2CSA, a ligand that binds to placental trophoblasts, causing IE to accumulate in the placenta. Resulting inflammation and pathology increases a woman’s risk of anemia...... to 28 malarial antigens and used the data to develop statistical models for predicting if a woman has sufficient immunity to prevent PM. Methods Archival plasma samples from 1377 women were screened in a bead-based multiplex assay for Ab to 17 VAR2CSA-associated antigens (full length VAR2CSA (FV2), DBL...... in the following seven statistical approaches: logistic regression full model, logistic regression reduced model, recursive partitioning, random forests, linear discriminant analysis, quadratic discriminant analysis, and support vector machine. Results The best and simplest model proved to be the logistic...
Yoshida, Shigeto; Kondoh, Daisuke; Arai, Eriko; Matsuoka, Hiroyuki; Seki, Chisato; Tanaka, Takao; Okada, Masaji; Ishii, Akira
The display of foreign proteins on the surface of baculovirus virions has provided a tool for the analysis of protein-protein interactions and for cell-specific targeting in gene transfer applications. To evaluate the baculovirus display system as a vaccine vehicle, we have generated a recombinant baculovirus (AcNPV-CSPsurf) that displays rodent malaria Plasmodium berghei circumsporozoite protein (PbCSP) on the virion surface as a fusion protein with the major baculovirus envelope glycoprotein gp64. The PbCSP-gp64 fusion protein was incorporated and oligomerized on the virion surface and led to a 12-fold increase in the binding activity of AcNPV-CSPsurf virions to HepG2 cells. Immunization with adjuvant-free AcNPV-CSPsurf virions induced high levels of antibodies and gamma interferon-secreting cells against PbCSP and protected 60% of mice against sporozoite challenge. These data demonstrate that AcNPV-CSPsurf displays sporozoite-like PbCSP on the virion surface and possesses dual potentials as a malaria vaccine candidate and a liver-directed gene delivery vehicle
Full Text Available Malaria parasite transmission requires differentiation of male and female gametocytes into gametes within a mosquito following a blood meal. A mosquito-derived molecule, xanthurenic acid (XA, can trigger gametogenesis, but the signalling events controlling this process in the human malaria parasite Plasmodium falciparum remain unknown. A role for cGMP was revealed by our observation that zaprinast (an inhibitor of phosphodiesterases that hydrolyse cGMP stimulates gametogenesis in the absence of XA. Using cGMP-dependent protein kinase (PKG inhibitors in conjunction with transgenic parasites expressing an inhibitor-insensitive mutant PKG enzyme, we demonstrate that PKG is essential for XA- and zaprinast-induced gametogenesis. Furthermore, we show that intracellular calcium (Ca2+ is required for differentiation and acts downstream of or in parallel with PKG activation. This work defines a key role for PKG in gametogenesis, elucidates the hierarchy of signalling events governing this process in P. falciparum, and demonstrates the feasibility of selective inhibition of a crucial regulator of the malaria parasite life cycle.
Thompson, Joanne; Fernandez-Reyes, Delmiro; Sharling, Lisa; Moore, Sally G; Eling, Wijnand M; Kyes, Sue A; Newbold, Christopher I; Kafatos, Fotis C; Janse, Chris J; Waters, Andrew P
The Cysteine Repeat Modular Proteins (PCRMP1-4) of Plasmodium, are encoded by a small gene family that is conserved in malaria and other Apicomplexan parasites. They are very large, predicted surface proteins with multipass transmembrane domains containing motifs that are conserved within families of cysteine-rich, predicted surface proteins in a range of unicellular eukaryotes, and a unique combination of protein-binding motifs, including a >100 kDa cysteine-rich modular region, an epidermal growth factor-like domain and a Kringle domain. PCRMP1 and 2 are expressed in life cycle stages in both the mosquito and vertebrate. They colocalize with PfEMP1 (P. falciparum Erythrocyte Membrane Antigen-1) during its export from P. falciparum blood-stage parasites and are exposed on the surface of haemolymph- and salivary gland-sporozoites in the mosquito, consistent with a role in host tissue targeting and invasion. Gene disruption of pcrmp1 and 2 in the rodent malaria model, P. berghei, demonstrated that both are essential for transmission of the parasite from the mosquito to the mouse and has established their discrete and important roles in sporozoite targeting to the mosquito salivary gland. The unprecedented expression pattern and structural features of the PCRMPs thus suggest a variety of roles mediating host-parasite interactions throughout the parasite life cycle.
Baldwin, Michael; Russo, Crystal; Li, Xuerong; Chishti, Athar H.
Highlights: • PfSPP is an ER resident protease. • PfSPP is expressed both as a monomer and dimer. • The signal peptide of HSP101 is the first known substrate of PfSPP. • Reduced PfSPP activity may significantly affect ER homeostasis. - Abstract: Previously we described the identification of a Plasmodium falciparum signal peptide peptidase (PfSPP) functioning at the blood stage of malaria infection. Our studies also demonstrated that mammalian SPP inhibitors prevent malaria parasite growth at the late-ring/early trophozoite stage of intra-erythrocytic development. Consistent with its role in development, we tested the hypothesis that PfSPP functions at the endoplasmic reticulum of P.falciparum where it cleaves membrane-bound signal peptides generated following the enzyme activity of signal peptidase. The localization of PfSPP to the endoplasmic reticulum was confirmed by immunofluorescence microscopy and immunogold electron microscopy. Biochemical analysis indicated the existence of monomer and dimer forms of PfSPP in the parasite lysate. A comprehensive bioinformatics screen identified several candidate PfSPP substrates in the parasite genome. Using an established transfection based in vivo luminescence assay, malaria heat shock protein 101 (HSP101) was identified as a substrate of PfSPP, and partial inhibition of PfSPP correlated with the emergence of gametocytes. This finding unveils the first known substrate of PfSPP, and provides new perspectives for the function of intra-membrane proteolysis at the erythrocyte stage of malaria parasite life cycle
Baldwin, Michael; Russo, Crystal; Li, Xuerong [Department of Developmental, Molecular and Chemical Biology, Tufts University School of Medicine, Boston, MA 02111 (United States); Chishti, Athar H., E-mail: email@example.com [Department of Developmental, Molecular and Chemical Biology, Tufts University School of Medicine, Boston, MA 02111 (United States); Sackler School of Graduate Biomedical Sciences, Programs in Physiology, Pharmacology, and Microbiology, Tufts University School of Medicine, Boston, MA 02111 (United States)
Highlights: • PfSPP is an ER resident protease. • PfSPP is expressed both as a monomer and dimer. • The signal peptide of HSP101 is the first known substrate of PfSPP. • Reduced PfSPP activity may significantly affect ER homeostasis. - Abstract: Previously we described the identification of a Plasmodium falciparum signal peptide peptidase (PfSPP) functioning at the blood stage of malaria infection. Our studies also demonstrated that mammalian SPP inhibitors prevent malaria parasite growth at the late-ring/early trophozoite stage of intra-erythrocytic development. Consistent with its role in development, we tested the hypothesis that PfSPP functions at the endoplasmic reticulum of P.falciparum where it cleaves membrane-bound signal peptides generated following the enzyme activity of signal peptidase. The localization of PfSPP to the endoplasmic reticulum was confirmed by immunofluorescence microscopy and immunogold electron microscopy. Biochemical analysis indicated the existence of monomer and dimer forms of PfSPP in the parasite lysate. A comprehensive bioinformatics screen identified several candidate PfSPP substrates in the parasite genome. Using an established transfection based in vivo luminescence assay, malaria heat shock protein 101 (HSP101) was identified as a substrate of PfSPP, and partial inhibition of PfSPP correlated with the emergence of gametocytes. This finding unveils the first known substrate of PfSPP, and provides new perspectives for the function of intra-membrane proteolysis at the erythrocyte stage of malaria parasite life cycle.
January Weiner 3rd
Full Text Available In order to combat the on-going malaria epidemic, discovery of new drug targets remains vital. Proteins that are essential to survival and specific to malaria parasites are key candidates. To survive within host cells, the parasites need to acquire nutrients and dispose of waste products across multiple membranes. Additionally, like all eukaryotes, they must redistribute ions and organic molecules between their various internal membrane bound compartments. Membrane transport proteins mediate all of these processes and are considered important mediators of drug resistance as well as drug targets in their own right. Recently, using advanced experimental genetic approaches and streamlined life cycle profiling, we generated a large collection of Plasmodium berghei gene deletion mutants and assigned essential gene functions, highlighting potential targets for prophylactic, therapeutic, and transmission-blocking anti-malarial drugs. Here, we present a comprehensive orthology assignment of all Plasmodium falciparum putative membrane transport proteins and provide a detailed overview of the associated essential gene functions obtained through experimental genetics studies in human and murine model parasites. Furthermore, we discuss the phylogeny of selected potential drug targets identified in our functional screen. We extensively discuss the results in the context of the functional assignments obtained using gene targeting available to date.
Moreira, Cristina K.; Naissant, Bernina; Coppi, Alida; Bennett, Brandy L.; Aime, Elena; Franke-Fayard, Blandine; Janse, Chris J.; Coppens, Isabelle; Sinnis, Photini; Templeton, Thomas J.
The phist gene family has members identified across the Plasmodium genus, defined by the presence of a domain of roughly 150 amino acids having conserved aromatic residues and an all alpha-helical structure. The family is highly amplified in P. falciparum, with 65 predicted genes in the genome of the 3D7 isolate. In contrast, in the rodent malaria parasite P. berghei 3 genes are identified, one of which is an apparent pseudogene. Transcripts of the P. berghei phist genes are predominant in schizonts, whereas in P. falciparum transcript profiles span different asexual blood stages and gametocytes. We pursued targeted disruption of P. berghei phist genes in order to characterize a simplistic model for the expanded phist gene repertoire in P. falciparum. Unsuccessful attempts to disrupt P. berghei PBANKA_114540 suggest that this phist gene is essential, while knockout of phist PBANKA_122900 shows an apparent normal progression and non-essential function throughout the life cycle. Epitope-tagging of P. falciparum and P. berghei phist genes confirmed protein export to the erythrocyte cytoplasm and localization with a punctate pattern. Three P. berghei PEXEL/HT-positive exported proteins exhibit at least partial co-localization, in support of a common vesicular compartment in the cytoplasm of erythrocytes infected with rodent malaria parasites. PMID:27022937
Wright, Katherine E; Hjerrild, Kathryn A; Bartlett, Jonathan; Douglas, Alexander D; Jin, Jing; Brown, Rebecca E; Illingworth, Joseph J; Ashfield, Rebecca; Clemmensen, Stine B; de Jongh, Willem A; Draper, Simon J; Higgins, Matthew K
Invasion of host erythrocytes is essential to the life cycle of Plasmodium parasites and development of the pathology of malaria. The stages of erythrocyte invasion, including initial contact, apical reorientation, junction formation, and active invagination, are directed by coordinated release of specialized apical organelles and their parasite protein contents. Among these proteins, and central to invasion by all species, are two parasite protein families, the reticulocyte-binding protein homologue (RH) and erythrocyte-binding like proteins, which mediate host-parasite interactions. RH5 from Plasmodium falciparum (PfRH5) is the only member of either family demonstrated to be necessary for erythrocyte invasion in all tested strains, through its interaction with the erythrocyte surface protein basigin (also known as CD147 and EMMPRIN). Antibodies targeting PfRH5 or basigin efficiently block parasite invasion in vitro, making PfRH5 an excellent vaccine candidate. Here we present crystal structures of PfRH5 in complex with basigin and two distinct inhibitory antibodies. PfRH5 adopts a novel fold in which two three-helical bundles come together in a kite-like architecture, presenting binding sites for basigin and inhibitory antibodies at one tip. This provides the first structural insight into erythrocyte binding by the Plasmodium RH protein family and identifies novel inhibitory epitopes to guide design of a new generation of vaccines against the blood-stage parasite.
Godonoga, Maia; Lin, Ting-Yu; Oshima, Azusa; Sumitomo, Koji; Tang, Marco S. L.; Cheung, Yee-Wai; Kinghorn, Andrew B.; Dirkzwager, Roderick M.; Zhou, Cunshan; Kuzuya, Akinori; Tanner, Julian A.; Heddle, Jonathan G.
DNA aptamers have potential for disease diagnosis and as therapeutics, particularly when interfaced with programmable molecular technology. Here we have combined DNA aptamers specific for the malaria biomarker Plasmodium falciparum lactate dehydrogenase (PfLDH) with a DNA origami scaffold. Twelve aptamers that recognise PfLDH were integrated into a rectangular DNA origami and atomic force microscopy demonstrated that the incorporated aptamers preserve their ability to specifically bind target protein. Captured PfLDH retained enzymatic activity and protein-aptamer binding was observed dynamically using high-speed AFM. This work demonstrates the ability of DNA aptamers to recognise a malaria biomarker whilst being integrated within a supramolecular DNA scaffold, opening new possibilities for malaria diagnostic approaches based on DNA nanotechnology. PMID:26891622
Esen, Meral; Kremsner, Peter G; Schleucher, Regina
Malaria is a major public health problem in Sub-Saharan Africa. In highly endemic regions infants, children and pregnant women are mostly affected. An effective malaria vaccine would complement existing malaria control strategies because it can be integrated in existing immunization programs easily....... Here we present the results of the first phase Ia clinical trial of GMZ2 adjuvanted in aluminium hydroxide. GMZ2 is a malaria vaccine candidate, designed upon the rationale to induce immune responses against asexual blood stages of Plasmodium falciparum similar to those encountered in semi...... is a safe and immunogenic malaria vaccine candidate suitable for further clinical development....
Kana, Ikhlaq Hussain; Adu, Bright; Tiendrebeogo, Régis Wendpayangde
febrile malaria. Similarly, GLURP-specific antibodies previously shown to be protective against febrile malaria in this same cohort were significantly associated with OP activity in this study. GLURP-specific antibodies recognized merozoites and also mediated OP activity. Conclusions.: These findings......Background.: Plasmodium species antigens accessible at the time of merozoite release are likely targets of biologically functional antibodies. Methods.: Immunoglobulin G (IgG) antibodies against intact merozoites were quantified in the plasma of Ghanaian children from a longitudinal cohort using...... a novel flow cytometry-based immunofluorescence assay. Functionality of these antibodies, as well as glutamate-rich protein (GLURP)-specific affinity-purified IgG from malaria hyperimmune Liberian adults, was assessed by the opsonic phagocytosis (OP) assay. Results.: Opsonic phagocytosis activity...
Full Text Available Malaria is a vector-borne infectious disease caused by unicellular, obligate intracellular parasites of the genus Plasmodium. During host switch the malaria parasite employs specialized latent stages that colonize the new host environment. Previous work has established that gametocytes, sexually differentiated stages that are taken up by the mosquito vector, control expression of genes required for mosquito colonization by translational repression. Sexual parasite development is controlled by a DEAD-box RNA helicase of the DDX6 family, termed DOZI. Latency of sporozoites, the transmission stage injected during an infectious blood meal, is controlled by the eIF2alpha kinase IK2, a general inhibitor of protein synthesis. Whether RNA-binding proteins participate in translational regulation in sporozoites remains to be studied. Here, we investigated the roles of two RNA-binding proteins of the Puf-family, Plasmodium Puf1 and Puf2, during sporozoite stage conversion. Our data reveal that, in the rodent malaria parasite P. berghei, Puf2 participates in the regulation of IK2 and inhibits premature sporozoite transformation. Inside mosquito salivary glands puf2⁻ sporozoites transform over time to round forms resembling early intra-hepatic stages. As a result, mutant parasites display strong defects in initiating a malaria infection. In contrast, Puf1 is dispensable in vivo throughout the entire Plasmodium life cycle. Our findings support the notion of a central role for Puf2 in parasite latency during switch between the insect and mammalian hosts.
Doorne, C.W. van; Eling, W.M.C.; Luyken, R.
Young male Wistar rats were fed a purified, vegetable, low-protein diet containing 6% protein from maize gluten and 2% from soy protein isolate, or comparable diets in which maize gluten was replaced partly or completely by the equivalent amount of a milk protein concentrate. Diets with adequate
Denise L. Doolan
Full Text Available Studies in mice have shown that immunity to malaria sporozoites is mediated primarily by citotoxic T lymphocytes (CTL specific for epitopes within the circumsporozoite (CS protein. Humans, had never been shown to generate CTL against any malaria or other parasite protein. The design of a sub-unit vaccine for humans ralies on the epitopes recognized by CTL being identified and polymorphisms therein being defined. We have developed a novel technique using an entire series of overlapping synthetic peptides to define the epitopes of the Plasmodium falciparum CS protein recognized by human CTL and have analyzed the sequence variation of the protein with respect to the identified CTL epitopic domain. We have demonstrated that some humans can indeed generate CTL. against the P. falciparum CS protein. Furthermore, the extent of variation observed for the CTL recognition domain is finite and the combination of peptides necessary for inclusion in a polyvalent vaccine may be small. If ways can be found to increase immune responsiveness, then a vaccine designed to stimulate CS protein-specific CTL activity may prevent malaria.
Full Text Available Malaria sporozoites must invade the salivary glands of mosquitoes for maturation before transmission to vertebrate hosts. The duration of the sporogonic cycle within the mosquitoes ranges from 10 to 21 days depending on the parasite species and temperature. During blood feeding salivary gland proteins are injected into the vertebrate host, along with malaria sporozoites in the case of an infected mosquito. To identify salivary gland proteins depleted after blood feeding of female Anopheles campestris-like, a potential malaria vector of Plasmodium vivax in Thailand, two-dimensional gel electrophoresis and nano-liquid chromatography-mass spectrometry techniques were used. Results showed that 19 major proteins were significantly depleted in three to four day-old mosquitoes fed on a first blood meal. For the mosquitoes fed the second blood meal on day 14 after the first blood meal, 14 major proteins were significantly decreased in amount. The significantly depleted proteins in both groups included apyrase, 5'-nucleotidase/apyrase, D7, D7-related 1, short form D7r1, gSG6, anti-platelet protein, serine/threonine-protein kinase rio3, putative sil1, cyclophilin A, hypothetical protein Phum_PHUM512530, AGAP007618-PA, and two non-significant hit proteins. To our knowledge, this study presents for the first time the salivary gland proteins that are involved in the second blood feeding on the day corresponding to the transmission period of the sporozoites to new mammalian hosts. This information serves as a basis for future work concerning the possible role of these proteins in the parasite transmission and the physiological processes that occur during the blood feeding.
Sor-suwan, Sriwatapron; Jariyapan, Narissara; Roytrakul, Sittiruk; Paemanee, Atchara; Phumee, Atchara; Phattanawiboon, Benjarat; Intakhan, Nuchpicha; Chanmol, Wetpisit; Bates, Paul A; Saeung, Atiporn; Choochote, Wej
Malaria sporozoites must invade the salivary glands of mosquitoes for maturation before transmission to vertebrate hosts. The duration of the sporogonic cycle within the mosquitoes ranges from 10 to 21 days depending on the parasite species and temperature. During blood feeding salivary gland proteins are injected into the vertebrate host, along with malaria sporozoites in the case of an infected mosquito. To identify salivary gland proteins depleted after blood feeding of female Anopheles campestris-like, a potential malaria vector of Plasmodium vivax in Thailand, two-dimensional gel electrophoresis and nano-liquid chromatography-mass spectrometry techniques were used. Results showed that 19 major proteins were significantly depleted in three to four day-old mosquitoes fed on a first blood meal. For the mosquitoes fed the second blood meal on day 14 after the first blood meal, 14 major proteins were significantly decreased in amount. The significantly depleted proteins in both groups included apyrase, 5'-nucleotidase/apyrase, D7, D7-related 1, short form D7r1, gSG6, anti-platelet protein, serine/threonine-protein kinase rio3, putative sil1, cyclophilin A, hypothetical protein Phum_PHUM512530, AGAP007618-PA, and two non-significant hit proteins. To our knowledge, this study presents for the first time the salivary gland proteins that are involved in the second blood feeding on the day corresponding to the transmission period of the sporozoites to new mammalian hosts. This information serves as a basis for future work concerning the possible role of these proteins in the parasite transmission and the physiological processes that occur during the blood feeding.
Ndiaye, Magatte; Sylla, Khadime; Sow, Doudou
Seasonal malaria chemoprevention (SMC) is defined as the intermittent administration of full treatment courses of an antimalarial drug to children during the peak of malaria transmission season with the aim of preventing malaria-associated mortality and morbidity. SMC using sulfadoxine-pyrimetham......Seasonal malaria chemoprevention (SMC) is defined as the intermittent administration of full treatment courses of an antimalarial drug to children during the peak of malaria transmission season with the aim of preventing malaria-associated mortality and morbidity. SMC using sulfadoxine......-pyrimethamine (SP) combined with amodiaquine (AQ) is a promising strategy to control malaria morbidity in areas of highly seasonal malaria transmission. However, a concern is whether SMC can delay the natural acquisition of immunity toward malaria parasites in areas with intense SMC delivery. To investigate this......, total IgG antibody (Ab) responses to Plasmodium falciparum antigens glutamate-rich protein R0 (GLURP-R0) and apical membrane antigen 1 (AMA-1) were measured by enzyme-linked immunosorbent assay in Senegalese children under the age of 10 years in 2010 living in Saraya and Velingara districts (with SMC...
Dodoo, D; Theander, T G; Kurtzhals, J A
malaria season in April and after the season in November. Using enzyme-linked immunosorbent assay, we measured antibody responses to recombinant gluthathione S-transferase-PfMSP119 fusion proteins corresponding to the Wellcome and MAD20 allelic variants in these samples. Prevalence of antibodies......The 19-kDa conserved C-terminal part of the Plasmodium falciparum merozoite surface protein 1 (PfMSP119) is a malaria vaccine candidate antigen, and human antibody responses to PfMSP119 have been associated with protection against clinical malaria. In this longitudinal study carried out in an area...
Full Text Available In a genome-wide screen for alpha-helical coiled coil motifs aiming at structurally defined vaccine candidates we identified PFF0165c. This protein is exported in the trophozoite stage and was named accordingly Trophozoite exported protein 1 (Tex1. In an extensive preclinical evaluation of its coiled coil peptides Tex1 was identified as promising novel malaria vaccine candidate providing the rational for a comprehensive cell biological characterization of Tex1. Antibodies generated against an intrinsically unstructured N-terminal region of Tex1 and against a coiled coil domain were used to investigate cytological localization, solubility and expression profile. Co-localization experiments revealed that Tex1 is exported across the parasitophorous vacuole membrane and located to Maurer's clefts. Change in location is accompanied by a change in solubility: from a soluble state within the parasite to a membrane-associated state after export to Maurer's clefts. No classical export motifs such as PEXEL, signal sequence/anchor or transmembrane domain was identified for Tex1.
Hallée, Stéphanie; Thériault, Catherine; Gagnon, Dominic; Kehrer, Jessica; Frischknecht, Friedrich; Mair, Gunnar R; Richard, Dave
Compared with other eukaryotic cell types, malaria parasites appear to possess a more rudimentary Golgi apparatus being composed of dispersed, unstacked cis and trans-cisternae. Despite playing a central role in the secretory pathway of the parasite, few Plasmodium Golgi resident proteins have been characterised. We had previously identified a new Golgi resident protein of unknown function, which we had named Golgi Protein 1, and now show that it forms a complex with a previously uncharacterised transmembrane protein (Golgi Protein 2, GP2). The Golgi Protein complex localises to the cis-Golgi throughout the erythrocytic cycle and potentially also during the mosquito stages. Analysis of parasite strains where GP1 expression is conditionally repressed and/or the GP2 gene is inactivated reveals that though the Golgi protein complex is not essential at any stage of the parasite life cycle, it is important for optimal asexual development in the blood stages. © 2018 John Wiley & Sons Ltd.
Noedl, Harald; Attlmayr, Bernhard; Wernsdorfer, Walther H; Kollaritsch, Herwig; Miller, Robert S
With the spread of antimalarial drug resistance, simple and reliable tools for the assessment of antimalarial drug resistance, particularly in endemic regions and under field conditions, have become more important than ever before. We therefore developed a histidine-rich protein 2 (HRP2)-based drug sensitivity assay for testing of fresh isolates of Plasmodium falciparum in the field. In contrast to the HRP2 laboratory assay, the field assay uses a procedure that further simplifies the handling and culturing of malaria parasites by omitting centrifugation, washing, the use of serum, and dilution with uninfected red blood cells. A total of 40 fresh Plasmodium falciparum isolates were successfully tested for their susceptibility to dihydroartemisinin, mefloquine, quinine, and chloroquine (50% inhibitory concentration [IC50] = 3.43, 61.89, 326.75, and 185.31 nM, respectively). Results very closely matched those obtained with a modified World Health Organization schizont maturation assay (R2 = 0.96, P < 0.001; mean log difference at IC50 = 0.054).
Modupe, Dokunmu Titilope; Iyabo, Olasehinde Grace; Oladoke, Oladejo David; Oladeji, Olanrewaju; Abisola, Akinbobola; Ufuoma, Adjekukor Cynthia; Faith, Yakubu Omolara; Humphrey, Adebayo Abiodun
In recent years there has been a global decrease in the prevalence of malaria due to scaling up of control measures, hence global control efforts now target elimination and eradication of the disease. However, a major problem associated with elimination is asymptomatic reservoir of infection especially in endemic areas. This study aims to determine the efficiency of histidine rich protein II (HRP-2) based rapid diagnostic tests (RDT) for monitoring transmission intensities in an endemic community in Nigeria during the pre-elimination stage. Plasmodium falciparum asymptomatic malaria infection in healthy individuals and symptomatic cases were detected using HRP-2. RDT negative tests were re-checked by microscopy and by primer specific PCR amplification of merozoite surface protein 2 (msp-2) for asexual parasites and Pfs25 gene for gametocytes in selected samples to detect low level parasitemia undetectable by microscopy. The mean age of the study population (n=280) was 6.12 years [95% CI 5.16 - 7.08, range 0.5 - 55], parasite prevalence was 44.6% and 36.3% by microscopy and RDT respectively (p =0.056). The parasite prevalence of 61.5% in children aged >2 - 10 years was significantly higher than 3.7% rate in adults >18years (p malaria in endemic areas.
Brown, Alan; Turner, Louise; Christoffersen, Stig
The adhesion of Plasmodium falciparum-infected erythrocytes to human tissues or endothelium is central to the pathology caused by the parasite during malaria. It contributes to the avoidance of parasite clearance by the spleen and to the specific pathologies of cerebral and placental malaria....... The PfEMP1 family of adhesive proteins is responsible for this sequestration by mediating interactions with diverse human ligands. In addition, as the primary targets of acquired, protective immunity, the PfEMP1s are potential vaccine candidates. PfEMP1s contain large extracellular ectodomains made from......, intercellular adhesion molecule-1 (ICAM-1). We show through small angle x-ray scattering that IT4VAR13 is rigid, elongated, and monomeric. We also show that it interacts with ICAM-1 through the DBLß domain alone, forming a 1:1 complex. These studies provide a first low resolution structural view of a PfEMP1...
Ramaprasad, Abhinay; Pain, Arnab; Ravasi, Timothy
Malaria, caused by the protozoan parasite Plasmodium falciparum, affects around 225. million people yearly and a huge international effort is directed towards combating this grave threat to world health and economic development. Considerable
Liu, Xuewu; Wang, Yuanyuan; Liang, Jiao; Wang, Luojun; Qin, Na; Zhao, Ya; Zhao, Gang
Plasmodium falciparum is the most virulent malaria parasite capable of parasitizing human erythrocytes. The identification of genes related to this capability can enhance our understanding of the molecular mechanisms underlying human malaria and lead to the development of new therapeutic strategies for malaria control. With the availability of several malaria parasite genome sequences, performing computational analysis is now a practical strategy to identify genes contributing to this disease. Here, we developed and used a virtual genome method to assign 33,314 genes from three human malaria parasites, namely, P. falciparum, P. knowlesi and P. vivax, and three rodent malaria parasites, namely, P. berghei, P. chabaudi and P. yoelii, to 4605 clusters. Each cluster consisted of genes whose protein sequences were significantly similar and was considered as a virtual gene. Comparing the enriched values of all clusters in human malaria parasites with those in rodent malaria parasites revealed 115 P. falciparum genes putatively responsible for parasitizing human erythrocytes. These genes are mainly located in the chromosome internal regions and participate in many biological processes, including membrane protein trafficking and thiamine biosynthesis. Meanwhile, 289 P. berghei genes were included in the rodent parasite-enriched clusters. Most are located in subtelomeric regions and encode erythrocyte surface proteins. Comparing cluster values in P. falciparum with those in P. vivax and P. knowlesi revealed 493 candidate genes linked to virulence. Some of them encode proteins present on the erythrocyte surface and participate in cytoadhesion, virulence factor trafficking, or erythrocyte invasion, but many genes with unknown function were also identified. Cerebral malaria is characterized by accumulation of infected erythrocytes at trophozoite stage in brain microvascular. To discover cerebral malaria-related genes, fast Fourier transformation (FFT) was introduced to extract
Full Text Available Anopheline mosquitoes are the primary vectors of parasites in the genus Plasmodium, the causative agents of malaria. Malaria parasites undergo a series of complex transformations upon ingestion by the mosquito host. During this process, the physical barrier of the midgut epithelium, along with innate immune defenses, functionally restrict parasite development. Although these defenses have been studied for some time, the regulatory factors that control them are poorly understood. The protein kinase C (PKC gene family consists of serine/threonine kinases that serve as central signaling molecules and regulators of a broad spectrum of cellular processes including epithelial barrier function and immunity. Indeed, PKCs are highly conserved, ranging from 7 isoforms in Drosophila to 16 isoforms in mammals, yet none have been identified in mosquitoes. Despite conservation of the PKC gene family and their potential as targets for transmission-blocking strategies for malaria, no direct connections between PKCs, the mosquito immune response or epithelial barrier integrity are known. Here, we identify and characterize six PKC gene family members--PKCδ, PKCε, PKCζ, PKD, PKN, and an indeterminate conventional PKC--in Anopheles gambiae and Anopheles stephensi. Sequence and phylogenetic analyses of the anopheline PKCs support most subfamily assignments. All six PKCs are expressed in the midgut epithelia of A. gambiae and A. stephensi post-blood feeding, indicating availability for signaling in a tissue that is critical for malaria parasite development. Although inhibition of PKC enzymatic activity decreased NF-κB-regulated anti-microbial peptide expression in mosquito cells in vitro, PKC inhibition had no effect on expression of a panel of immune genes in the midgut epithelium in vivo. PKC inhibition did, however, significantly increase midgut barrier integrity and decrease development of P. falciparum oocysts in A. stephensi, suggesting that PKC
Cavanagh, D R; Elhassan, I M; Roper, C
Merozoite surface protein-1 (MSP-1) of Plasmodium falciparum is a malaria vaccine candidate Ag. Immunity to MSP-1 has been implicated in protection against infection in animal models. However, MSP-1 is a polymorphic protein and its immune recognition by humans following infection is not well unde...
Jairo Andres Fonseca
Full Text Available A malaria vaccine is a public health priority. In order to produce an effective vaccine, a multistage approach targeting both the blood and the liver stage infection is desirable. The vaccine candidates also need to induce balanced immune responses including antibodies, CD4+ and CD8+ T cells. Protein-based subunit vaccines like RTS,S are able to induce strong antibody response but poor cellular reactivity. Adenoviral vectors have been effective inducing protective CD8+ T cell responses in several models including malaria; nonetheless this vaccine platform exhibits a limited induction of humoral immune responses. Two approaches have been used to improve the humoral immunogenicity of recombinant adenovirus vectors, the use of heterologous prime-boost regimens with recombinant proteins or the genetic modification of the hypervariable regions (HVR of the capsid protein hexon to express B cell epitopes of interest. In this study, we describe the development of capsid modified Ad5 vectors that express a promiscuous Plasmodium yoelii T helper epitope denominated PyT53 within the hexon HVR2 region. Several regimens were tested in mice to determine the relevance of the hexon modification in enhancing protective immune responses induced by the previously described protein-based multi-stage experimental vaccine PyCMP. A heterologous prime-boost immunization regime that combines a hexon modified vector with transgenic expression of PyCMP followed by protein immunizations resulted in the induction of robust antibody and cellular immune responses in comparison to a similar regimen that includes a vector with unmodified hexon. These differences in immunogenicity translated into a better protective efficacy against both the hepatic and red blood cell stages of P. yoelii. To our knowledge, this is the first time that a hexon modification is used to deliver a promiscuous T cell epitope. Our data support the use of such modification to enhance the immunogenicity
Flanagan, Katie L; Wilson, Kirsty L; Plebanski, Magdalena
The pre-erythrocytic stage of infection by malaria parasites represents a key target for vaccines that aim to eradicate malaria. Two important broad immune evasion strategies that can interfere with vaccine efficacy include the induction of dendritic cell (DC) dysfunction and regulatory T cells (Tregs) by blood-stage malaria parasites, leading to inefficient priming of T cells targeting liver-stage infections. The parasite also uses 'surgical strike' strategies, whereby polymorphism in pre-erythrocytic antigens can interfere with host immunity. Specifically, we review how even single amino acid changes in T cell epitopes can lead to loss of binding to major histocompatibility complex (MHC), lack of cross-reactivity, or antagonism and immune interference, where simultaneous or sequential stimulation with related variants of the same T cell epitope can cause T cell anergy or the conversion of effector to immunosuppressive T cell phenotypes.
Jeremy Ryan De Silva
Full Text Available Malaria remains a major health threat in many parts of the globe and causes high mortality and morbidity with 214 million cases of malaria occurring globally in 2015. Recent studies have outlined potential diagnostic markers and vaccine candidates one of which is the merozoite surface protein (MSP-3. In this study, novel recombinant Plasmodium knowlesi MSP-3 was cloned, expressed and purified in an Escherichia coli system. Subsequently, the recombinant protein was evaluated for its sensitivity and specificity. The recombinant pkMSP-3 protein reacted with sera from patients with P. knowlesi infection in both Western blot (61% and ELISA (100%. Specificity-wise, pkMSP-3 did not react with healthy donor sera in either assay and only reacted with a few non-malarial parasitic patient sera in the ELISA assay (3 of 49. In conclusion, sensitivity and specificity of pkMSP-3 was found to be high in the ELISA and Western Blot assay and thus utilising both assays in tandem would provide the best sero-diagnostic result for P. knowlesi infection.
Elizabeth S Zuccala
Full Text Available Host cell infection by apicomplexan parasites plays an essential role in lifecycle progression for these obligate intracellular pathogens. For most species, including the etiological agents of malaria and toxoplasmosis, infection requires active host-cell invasion dependent on formation of a tight junction - the organising interface between parasite and host cell during entry. Formation of this structure is not, however, shared across all Apicomplexa or indeed all parasite lifecycle stages. Here, using an in silico integrative genomic search and endogenous gene-tagging strategy, we sought to characterise proteins that function specifically during junction-dependent invasion, a class of proteins we term invasins to distinguish them from adhesins that function in species specific host-cell recognition. High-definition imaging of tagged Plasmodium falciparum invasins localised proteins to multiple cellular compartments of the blood stage merozoite. This includes several that localise to distinct subcompartments within the rhoptries. While originating from the same organelle, however, each has very different dynamics during invasion. Apical Sushi Protein and Rhoptry Neck protein 2 release early, following the junction, whilst a novel rhoptry protein PFF0645c releases only after invasion is complete. This supports the idea that organisation of proteins within a secretory organelle determines the order and destination of protein secretion and provides a localisation-based classification strategy for predicting invasin function during apicomplexan parasite invasion.
Silvestrini, F.; Lasonder, E.; Olivieri, A.; Camarda, G.; Schaijk, B.C.L. van; Sanchez, M.; Younis Younis, S.; Sauerwein, R.W.; Alano, P.
Despite over a century of study of malaria parasites, parts of the Plasmodium falciparum life cycle remain virtually unknown. One of these is the early gametocyte stage, a round shaped cell morphologically similar to an asexual trophozoite in which major cellular transformations ensure subsequent
... Emergency Consultations, and General Public. Contact Us About Malaria Recommend on Facebook Tweet Share Compartir Malaria is ... from sub-Saharan Africa and South Asia. About Malaria Topics FAQs Frequently Asked Question, Incubation period, uncomplicated & ...
Tamborrini, Marco; Stoffel, Sabine A; Westerfeld, Nicole
In clinical trials, immunopotentiating reconstituted influenza virosomes (IRIVs) have shown great potential as a versatile antigen delivery platform for synthetic peptides derived from Plasmodium falciparum antigens. This study describes the immunogenicity of a virosomally-formulated recombinant ...... fusion protein comprising domains of the two malaria vaccine candidate antigens MSP3 and GLURP....
Shabani, Estela; Opoka, Robert O; Bangirana, Paul
The endothelial protein C receptor (EPCR) appears to play an important role in Plasmodium falciparum endothelial cell binding in severe malaria (SM). Despite consistent findings of elevated soluble EPCR (sEPCR) in other infectious diseases, field studies to date have provided conflicting data abo...
Magallón-Tejada, Ariel; Machevo, Sónia; Cisteró, Pau
Cytoadhesion of Plasmodium falciparum infected erythrocytes to gC1qR has been associated with severe malaria, but the parasite ligand involved is currently unknown. To assess if binding to gC1qR is mediated through the P. falciparum erythrocyte membrane protein 1 (PfEMP1) family, we analyzed...
Pratt-Riccio, Lilian Rose; Perce-da-Silva, Daiana de Souza; Lima-Junior, Josué da Costa
The genetic diversity displayed by Plasmodium falciparum, the most deadly Plasmodium species, is a significant obstacle for effective malaria vaccine development. In this study, we identified genetic polymorphisms in P. falciparum glutamate-rich protein (GLURP), which is currently being tested in...
Giha, Hayder A; Nasr, Amre; Ekström, Mattias
The role of inflammation in malaria pathogenesis is not fully understood, although C-reactive protein (CRP) may have a negative influence on host immunity to infections. An upstream polymorphism, -286 (C > T > A), in the CRP gene is known to influence CRP levels. In this study, a cohort of 192 Su...
Hussain, Tahir; Yogavel, Manickam; Sharma, Amit
Aminoacyl-tRNA synthetases (aaRSs) are housekeeping enzymes that couple cognate tRNAs with amino acids to transmit genomic information for protein translation. The Plasmodium falciparum nuclear genome encodes two P. falciparum methionyl-tRNA synthetases (PfMRS), termed PfMRS(cyt) and PfMRS(api). Phylogenetic analyses revealed that the two proteins are of primitive origin and are related to heterokonts (PfMRS(cyt)) or proteobacteria/primitive bacteria (PfMRS(api)). We show that PfMRS(cyt) localizes in parasite cytoplasm, while PfMRS(api) localizes to apicoplasts in asexual stages of malaria parasites. Two known bacterial MRS inhibitors, REP3123 and REP8839, hampered Plasmodium growth very effectively in the early and late stages of parasite development. Small-molecule drug-like libraries were screened against modeled PfMRS structures, and several "hit" compounds showed significant effects on parasite growth. We then tested the effects of the hit compounds on protein translation by labeling nascent proteins with (35)S-labeled cysteine and methionine. Three of the tested compounds reduced protein synthesis and also blocked parasite growth progression from the ring stage to the trophozoite stage. Drug docking studies suggested distinct modes of binding for the three compounds, compared with the enzyme product methionyl adenylate. Therefore, this study provides new targets (PfMRSs) and hit compounds that can be explored for development as antimalarial drugs. Copyright © 2015, American Society for Microbiology. All Rights Reserved.
Tetriana, D.; Syaifudin, M.
Sporozoite is a step of malaria parasitic live cycle that is most invasive and appropriate vaccine candidate. Result of experiments showed that malaria vaccine created by attenuating Plasmodium sp sporozoites with gamma rays was proven more effective. Study on the effects of irradiation to the profiles of protein in vaccine development is also important. The aim of this research was to examine the protein profile of salivary glands in sporozoite infected Anopheles sp post gamma irradiation using Sodium dodecyl sulphate-polyacrylamide gel electrophoresis (SDS-PAGE) technique. Examination covered the infection of Anopheles sp with Plasmodium sp, maintenance of infected mosquitoes for 14-16 days to obtain sporozoites, in vivo - in vitro irradiation of mosquitoes, preparation of salivary glands, electrophoresis on 10% SDS-PAGE, and Commassie blue staining. Results showed a different protein profile of infected and non infected salivary glands of Anopheles sp. There was additional protein band numbers at higher dose of irradiation (200 Gy) from sporozoite protein of P. berghei (MW 62 kDa). However, no difference of the profiles of circumsporozoite protein (CSP) observed among gamma irradiation doses of 150, 175 and 200 Gy. These results provide basic information that would lead to further study on the role of sporozoite proteins in malaria vaccine development. (author)
Seiler, Roland; Oo, Htoo Zarni; Tortora, Davide
the malaria parasite Plasmodium falciparum, we can target these sugar chains, and our results showed a significant antitumor effect in cisplatin-resistant bladder cancer. This novel treatment paradigm provides therapeutic access to bladder cancers not responding to cisplatin.......BACKGROUND: Although cisplatin-based neoadjuvant chemotherapy (NAC) improves survival of unselected patients with muscle-invasive bladder cancer (MIBC), only a minority responds to therapy and chemoresistance remains a major challenge in this disease setting. OBJECTIVE: To investigate the clinical...... significance of oncofetal chondroitin sulfate (ofCS) glycosaminoglycan chains in cisplatin-resistant MIBC and to evaluate these as targets for second-line therapy. DESIGN, SETTING, AND PARTICIPANTS: An ofCS-binding recombinant VAR2CSA protein derived from the malaria parasite Plasmodium falciparum (rVAR2...
Moon, Robert W.; Sharaf, Hazem; Hastings, Claire H.; Ho, Yung Shwen; Nair, Mridul; Rchiad, Zineb; Knuepfer, Ellen; Ramaprasad, Abhinay; Mohring, Franziska; Amir, Amirah; Yusuf, Noor A.; Hall, Joanna; Almond, Neil; Lau, Yee Ling; Pain, Arnab; Blackman, Michael J.; Holder, Anthony A.
The dominant cause of malaria in Malaysia is now Plasmodium knowlesi, a zoonotic parasite of cynomolgus macaque monkeys found throughout South East Asia. Comparative genomic analysis of parasites adapted to in vitro growth in either cynomolgus or human RBCs identified a genomic deletion that includes the gene encoding normocyte-binding protein Xa (NBPXa) in parasites growing in cynomolgus RBCs but not in human RBCs. Experimental deletion of the NBPXa gene in parasites adapted to growth in human RBCs (which retain the ability to grow in cynomolgus RBCs) restricted them to cynomolgus RBCs, demonstrating that this gene is selectively required for parasite multiplication and growth in human RBCs. NBPXa-null parasites could bind to human RBCs, but invasion of these cells was severely impaired. Therefore, NBPXa is identified as a key mediator of P. knowlesi human infection and may be a target for vaccine development against this emerging pathogen.
Moon, Robert W.
The dominant cause of malaria in Malaysia is now Plasmodium knowlesi, a zoonotic parasite of cynomolgus macaque monkeys found throughout South East Asia. Comparative genomic analysis of parasites adapted to in vitro growth in either cynomolgus or human RBCs identified a genomic deletion that includes the gene encoding normocyte-binding protein Xa (NBPXa) in parasites growing in cynomolgus RBCs but not in human RBCs. Experimental deletion of the NBPXa gene in parasites adapted to growth in human RBCs (which retain the ability to grow in cynomolgus RBCs) restricted them to cynomolgus RBCs, demonstrating that this gene is selectively required for parasite multiplication and growth in human RBCs. NBPXa-null parasites could bind to human RBCs, but invasion of these cells was severely impaired. Therefore, NBPXa is identified as a key mediator of P. knowlesi human infection and may be a target for vaccine development against this emerging pathogen.
IgG antibodies to endothelial protein C receptor-binding Cysteine-rich interdomain region domains of Plasmodium falciparum erythrocyte membrane protein 1 are acquired early in life in individuals exposed to malaria
Turner, Louise; Lavstsen, Thomas; Mmbando, Bruno P
Severe malaria syndromes are precipitated by Plasmodium falciparum parasites binding to endothelial receptors on the vascular lining. This binding is mediated by members of the highly variant P. falciparum erythrocyte membrane protein 1 (PfEMP1) family. We have previously identified a subset of Pf...
Christine R Collins
Full Text Available The malaria parasite replicates within an intraerythrocytic parasitophorous vacuole (PV. Eventually, in a tightly regulated process called egress, proteins of the PV and intracellular merozoite surface are modified by an essential parasite serine protease called PfSUB1, whilst the enclosing PV and erythrocyte membranes rupture, releasing merozoites to invade fresh erythrocytes. Inhibition of the Plasmodium falciparum cGMP-dependent protein kinase (PfPKG prevents egress, but the underlying mechanism is unknown. Here we show that PfPKG activity is required for PfSUB1 discharge into the PV, as well as for release of distinct merozoite organelles called micronemes. Stimulation of PfPKG by inhibiting parasite phosphodiesterase activity induces premature PfSUB1 discharge and egress of developmentally immature, non-invasive parasites. Our findings identify the signalling pathway that regulates PfSUB1 function and egress, and raise the possibility of targeting PfPKG or parasite phosphodiesterases in therapeutic approaches to dysregulate critical protease-mediated steps in the parasite life cycle.
Genito, Christopher J; Beck, Zoltan; Phares, Timothy W; Kalle, Fanta; Limbach, Keith J; Stefaniak, Maureen E; Patterson, Noelle B; Bergmann-Leitner, Elke S; Waters, Norman C; Matyas, Gary R; Alving, Carl R; Dutta, Sheetij
Malaria caused by Plasmodium falciparum continues to threaten millions of people living in the tropical parts of the world. A vaccine that confers sterile and life-long protection remains elusive despite more than 30years of effort and resources invested in solving this problem. Antibodies to a malaria vaccine candidate circumsporozoite protein (CSP) can block invasion and can protect humans against malaria. We have manufactured the Falciparum Malaria Protein-013 (FMP013) vaccine based on the nearly full-length P. falciparum CSP 3D7 strain sequence. We report here immunogenicity and challenge data on FMP013 antigen in C57BL/6 mice formulated with two novel adjuvants of the Army Liposome Formulation (ALF) series and a commercially available adjuvant Montanide ISA 720 (Montanide) as a control. ALF is a liposomal adjuvant containing a synthetic monophosphoryl lipid A (3D-PHAD®). In our study, FMP013 was adjuvanted with ALF alone, ALF containing aluminum hydroxide (ALFA) or ALF containing QS-21 (ALFQ). Adjuvants ALF and ALFA induced similar antibody titers and protection against transgenic parasite challenge that were comparable to Montanide. ALFQ was superior to the other three adjuvants as it induced higher antibody titers with improved boosting after the third immunization, higher serum IgG2c titers, and enhanced protection. FMP013+ALFQ also augmented the numbers of splenic germinal center-derived activated B-cells and antibody secreting cells compared to Montanide. Further, FMP013+ALFQ induced antigen-specific IFN-γ ELISPOT activity, CD4 + T-cells and a T H 1-biased cytokine profile. These results demonstrate that soluble CSP can induce a potent and sterile protective immune response when formulated with the QS-21 containing adjuvant ALFQ. Comparative mouse immunogenicity data presented here were used as the progression criteria for an ongoing non-human primate study and a regulatory toxicology study in preparation for a controlled human malaria infection (CHMI
Qian, Feng; Wu, Yimin; Muratova, Olga; Zhou, Hong; Dobrescu, Gelu; Duggan, Peter; Lynn, Lambert; Song, Guanhong; Zhang, Yanling; Reiter, Karine; MacDonald, Nicholas; Narum, David L.; Long, Carole A.; Miller, Louis H.; Saul, Allan
Conjugation of polysaccharides to carrier proteins has been a successful approach for producing safe and effective vaccines. In an attempt to increase the immunogenicity of two malarial vaccine candidate proteins of Plasmodium falciparum, apical membrane antigen 1 (AMA1) for blood stage vaccines and surface protein 25 (Pfs25) for mosquito stage vaccines, each was chemically conjugated to the mutant, nontoxic Pseudomonas aeruginosa ExoProtein A (rEPA). AMA1 is a large (66 kD) relatively good i...
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Wang, Christian W; Magistrado, Pamela A; Nielsen, Morten A
transcribed in the VAR2CSA-expressing parasite line. In addition, two rif genes were found transcribed at early and late intra-erythrocyte stages independently of var gene transcription. Rif genes are organised in groups and inter-genomic conserved gene families, suggesting that RIFIN sub-groups may have......Plasmodium falciparum variant surface antigens (VSA) are targets of protective immunity to malaria. Plasmodium falciparum erythrocyte membrane protein 1 (PfEMP1) and repetitive interspersed family (RIFIN) proteins are encoded by the two variable multigene families, var and rif genes, respectively...... novel rif gene groups, rifA1 and rifA2, containing inter-genomic conserved rif genes, were identified. All rifA1 genes were orientated head-to-head with a neighbouring Group A var gene whereas rifA2 was present in all parasite genomes as a single copy gene with a unique 5' untranslated region. Rif...
Magistrado, Pamela A; Lusingu, John; Vestergaard, Lasse S
where P. falciparum is endemic, parasites causing severe malaria and malaria in young children with limited immunity tend to express semiconserved PfEMP1 molecules encoded by group A var genes. Here we investigated antibody responses of Tanzanians who were 0 to 19 years old to PF11_0008, a group A Pf...
Amy R Noe
Full Text Available The circumsporozoite protein (CSP of Plasmodium falciparum is a major surface protein, which forms a dense coat on the sporozoite's surface. Preclinical research on CSP and clinical evaluation of a CSP fragment-based RTS, S/AS01 vaccine have demonstrated a modest degree of protection against P. falciparum, mediated in part by humoral immunity and in part by cell-mediated immunity. Given the partial protective efficacy of the RTS, S/AS01 vaccine in a recent Phase 3 trial, further improvement of CSP-based vaccines is crucial. In this report, we describe the preclinical development of a full-length, recombinant CSP (rCSP-based vaccine candidate against P. falciparum malaria suitable for current Good Manufacturing Practice (cGMP production. Utilizing a novel high-throughput Pseudomonas fluorescens expression platform, we demonstrated greater efficacy of full-length rCSP as compared to N-terminally truncated versions, rapidly down-selected a promising lead vaccine candidate, and developed a high-yield purification process to express immunologically active, intact antigen for clinical trial material production. The rCSP, when formulated with various adjuvants, induced antigen-specific antibody responses as measured by enzyme-linked immunosorbent assay (ELISA and immunofluorescence assay (IFA, as well as CD4+ T-cell responses as determined by ELISpot. The adjuvanted rCSP vaccine conferred protection in mice when challenged with transgenic P. berghei sporozoites containing the P. falciparum repeat region of CSP. Furthermore, heterologous prime/boost regimens with adjuvanted rCSP and an adenovirus type 35-vectored CSP (Ad35CS showed modest improvements in eliciting CSP-specific T-cell responses and anti-malarial protection, depending on the order of vaccine delivery. Collectively, these data support the importance of further clinical development of adjuvanted rCSP, either as a stand-alone product or as one of the components in a heterologous prime
Hansen, Daniel Aaen
Malaria is a life threatening disease found in tropical and subtropical regions of the world. Each year it kills 781 000 individuals; most of them are children under the age of five in sub-Saharan Africa. The most severe form of malaria in humans is caused by the parasite Plasmodium falciparum......, which is the subject of the first part of this thesis. The PfEMP1 protein which is encoded by the highly variablevargene family is important in the pathogenesis and immune evasion of malaria parasites. We analyzed and classified these genes based on the upstream sequence in seven......Plasmodium falciparumclones. We show that the amount of nucleotide diversity is just as big within each clone as it is between the clones. DNA methylation is an important epigenetic mark in many eukaryotic species. We are studying DNA methylation in the malaria parasitePlasmodium falciparum. The work is still in progress...
Expression, Purification and Characterization of GMZ2'.10C, a Complex Disulphide-Bonded Fusion Protein Vaccine Candidate against the Asexual and Sexual Life-Stages of the Malaria-Causing Plasmodium falciparum Parasite
Mistarz, U.H.; Singh, S.K; Nguyen, T.; Roeffen, W.; Lissau, C.; Madsen, S.M.; Vrang, A.; Tiendrebeogo, R.W.; Kana, I.H.; Sauerwein, R.W.; Theisen, M.; Rand, K.D.
PURPOSE: Production and characterization of a chimeric fusion protein (GMZ2'.10C) which combines epitopes of key malaria parasite antigens: glutamate-rich protein (GLURP), merozoite surface protein 3 (MSP3), and the highly disulphide bonded Pfs48/45 (10C). GMZ2'.10C is a potential candidate for a
Full Text Available Abstract Background The 200 kDa merozoite surface protein 1 (MSP-1 of malaria parasites, a strong vaccine candidate, plays a key role during erythrocyte invasion and is a target of host protective immune response. Plasmodium vivax, the most widespread human malaria parasite, is closely related to parasites that infect Asian Old World monkeys, and has been considered to have become a parasite of man by host switch from a macaque malaria parasite. Several Asian monkey parasites have a range of natural hosts. The same parasite species shows different disease manifestations among host species. This suggests that host immune responses to P. vivax-related malaria parasites greatly differ among host species (albeit other factors. It is thus tempting to invoke that a major immune target parasite protein such as MSP-1 underwent unique evolution, depending on parasite species that exhibit difference in host range and host specificity. Results We performed comparative phylogenetic and population genetic analyses of the gene encoding MSP-1 (msp1 from P. vivax and nine P. vivax-related simian malaria parasites. The inferred phylogenetic tree of msp1 significantly differed from that of the mitochondrial genome, with a striking displacement of P. vivax from a position close to P. cynomolgi in the mitochondrial genome tree to an outlier of Asian monkey parasites. Importantly, positive selection was inferred for two ancestral branches, one leading to P. inui and P. hylobati and the other leading to P. vivax, P. fieldi and P. cynomolgi. This ancestral positive selection was estimated to have occurred three to six million years ago, coinciding with the period of radiation of Asian macaques. Comparisons of msp1 polymorphisms between P. vivax, P. inui and P. cynomolgi revealed that while some positively selected amino acid sites or regions are shared by these parasites, amino acid changes greatly differ, suggesting that diversifying selection is acting species
Qian, Feng; Wu, Yimin; Muratova, Olga; Zhou, Hong; Dobrescu, Gelu; Duggan, Peter; Lynn, Lambert; Song, Guanhong; Zhang, Yanling; Reiter, Karine; MacDonald, Nicholas; Narum, David L; Long, Carole A; Miller, Louis H; Saul, Allan; Mullen, Gregory E D
Conjugation of polysaccharides to carrier proteins has been a successful approach for producing safe and effective vaccines. In an attempt to increase the immunogenicity of two malarial vaccine candidate proteins of Plasmodium falciparum, apical membrane antigen 1 (AMA1) to a blood stage vaccine candidate and surface protein 25 (Pfs25) a mosquito stage vaccine candidate, were each independently chemically conjugated to the mutant, nontoxic Pseudomonas aeruginosa ExoProtein A (rEPA). AMA1 is a large (66kD) relatively good immunogen in mice; Pfs25 is a poorly immunogenic protein when presented on alum to mice. Mice were immunized on days 0 and 28 with AMA1- or Pfs25-rEPA conjugates or unconjugated AMA1 or Pfs25, all formulated on Alhydrogel. Remarkably, sera from mice 14 days after the second immunization with Pfs25-rEPA conjugates displayed over a 1000-fold higher antibody titers as compared to unconjugated Pfs25. In contrast, AMA1 conjugated under the same conditions induced only a three-fold increase in antibody titers. When tested for functional activity, antibodies elicited by the AMA1-rEPA inhibited invasion of erythrocytes by blood-stage parasites and antibodies elicited by the Pfs25-rEPA conjugates blocked the development of the sexual stage parasites in the mosquito midgut. These results demonstrate that conjugation to rEPA induces a marked improvement in the antibody titer in mice for the poor immunogen (Pfs25) and for the larger protein (AMA1). These conjugates now need to be tested in humans to determine if mice are predictive of the response in humans.
Mar 8, 2010 ... antigenic polymorphism, shedding of parts of parasite proteins, cross-reactive epitopes of antigens of ... Due to the lack of HLA molecules on the surface of the .... Susceptibility and death rates in P. falciparum malaria are.
Full Text Available BACKGROUND: Surrogate markers of protective immunity to malaria in humans are needed to rationalize malaria vaccine discovery and development. In an effort to identify such markers, and thereby provide a clue to the complex equation malaria vaccine development is facing, we investigated the relationship between protection acquired through exposure in the field with naturally occurring immune responses (i.e., induced by the parasite to molecules that are considered as valuable vaccine candidates. METHODS AND FINDINGS: We analyzed, under comparative conditions, the antibody responses of each of six isotypes to five leading malaria vaccine candidates in relation to protection acquired by exposure to natural challenges in 217 of the 247 inhabitants of the African village of Dielmo, Senegal (96 children and 121 older adolescents and adults. The status of susceptibility or resistance to malaria was determined by active case detection performed daily by medical doctors over 6 y from a unique follow-up study of this village. Of the 30 immune responses measured, only one, antibodies of the IgG3 isotype directed to merozoite surface protein 3 (MSP3, was strongly associated with clinical protection against malaria in all age groups, i.e., independently of age. This immunological parameter had a higher statistical significance than the sickle cell trait, the strongest factor of protection known against Plasmodium falciparum. A single determination of antibody was significantly associated with the clinical outcome over six consecutive years in children submitted to massive natural parasite challenges by mosquitoes (over three parasite inoculations per week. Finally, the target epitopes of these antibodies were found to be fully conserved. CONCLUSIONS: Since anti-MSP3 IgG3 antibodies can naturally develop along with protection against P. falciparum infection in young children, our results provide the encouraging indication that these antibodies should be
Mota Maria M
Full Text Available Abstract Background The Plasmodium Cysteine Repeat Modular Proteins (PCRMP are a family of four conserved proteins of malaria parasites, that contain a number of motifs implicated in host-parasite interactions. Analysis of mutants of the rodent parasite Plasmodium berghei lacking expression of PCRMP1 or 2 showed that these proteins are essential for targeting of P. berghei sporozoites to the mosquito salivary gland and, hence, for transmission from the mosquito to the mouse. Methods In this work, the role of the remaining PCRMP family members, PCRMP3 and 4, has been investigated throughout the Plasmodium life cycle by generation and analysis of P. berghei gene deletion mutants, Δpcrmp3 and Δpcrmp4. The role of PCRMP members during the transmission and hepatic stages of the Plasmodium lifecycle has been evaluated by light- and electron microscopy and by analysis of liver stage development in HEPG2 cells in vitro and by infecting mice with mutant sporozoites. In addition, mice were immunized with live Δpcrmp3 and Δpcrmp4 sporozoites to evaluate their immunization potential as a genetically-attenuated parasite-based vaccine. Results Disruption of pcrmp3 and pcrmp4 in P. berghei revealed that they are also essential for transmission of the parasite through the mosquito vector, although acting in a distinct way to pbcrmp1 and 2. Mutants lacking expression of PCRMP3 or PCRMP4 show normal blood stage development and oocyst formation in the mosquito and develop into morphologically normal sporozoites, but these have a defect in egress from oocysts and do not enter the salivary glands. Sporozoites extracted from oocysts perform gliding motility and invade and infect hepatocytes but do not undergo further development and proliferation. Furthermore, the study shows that immunization with Δcrmp3 and Δcrmp4 sporozoites does not confer protective immunity upon subsequent challenge. Conclusions PCRMP3 and 4 play multiple roles during the Plasmodium life
Jessen, Leon Eyrich
Malaria is an infectious disease caused by a protozoan parasite of the genus Plasmodium, which is transferred by female Anopheles mosquitos. WHO estimates that in 2012 there were 207 million cases of malaria, of which 627,000 were fatal. People living in malaria-endemic areas, gradually acquire...... immunity with multiple infections. Placental malaria (PM) is caused by P. falciparum sequestering in the placenta of pregnant women due to the presence of novel receptors in the placenta. An estimated 200,000 infants die a year as a result of PM. In 2004 the specific protein responsible...... and development in the field of placental malaria vaccine development....
Carlos Hugo Zapata Zapata
Full Text Available La malaria Cerebral (MC es la complicación más frecuente de la malaria por P. falciparum; aproximadamente el 90% de las personas que la han padecido se recuperan completamente sin secuelas neurológicas. Aún no se conoce con claridad su patogénesis pero se han postulado cuatro hipótesis o mecanismos posibles: 1 citoadherencia y secuestro de glóbulos rojos parasitados en la microvasculatura cerebral; 2 formación de rosetas y aglutinación de glóbulos rojos parasitados; 3 producción de citoquinas y activación de segundos mensajeros y, 4 apertura de la barrera hematoencefálica. Sin embargo, queda un interrogante sin resolver aún: ¿qué proceso se lleva a cabo para que el parásito, desde el espacio microvascular, pueda interferir transitoriamente con la función cerebral? Recientemente se ha utilizado el precursor de la proteína b-Amiloide como un marcador de daño neuronal en MC; este precursor será de gran ayuda en futuras investigaciones realizadas en nuestro medio que aporten información para comprender la patogénesis de la MC. Is the most common complication of P. falciparum malaria; nearly 90% of people who have suffered CM can recover without neurological problems. Currently there are four hypotheses that explain pathogenesis of CM: cytoadherence and sequestering of parasitized red blood cells to cerebral capillaries; rosette formation and parasitized red blood cells agglutination; production of cytokines and activation of second messengers and opening of the blood-brain barrier. However the main question remains to be answered; how the host-parasite interaction in the vascular space interferes transiently with cerebral function? Recently, the beta amyloid precursor peptide has been employed as marker of neural injury in CM. It is expected that the beta amyloid precursor peptide will help to understand the pathogenesis of CM in complicated patients of endemic areas of Colombia.
Victor, Michala E; Bengtsson, Anja; Andersen, Gorm
-exposed epitopes are unknown. An insect cell and Escherichia coli based system was used to express single and double domains encoded by the pfd1235w var gene. The resulting recombinant proteins have been evaluated for yield and purity and their ability to induce rat antibodies, which react with the native PFD1235w...... PfEMP1 antigen expressed on 3D7PFD1235w-IE. Their recognition by human anti-malaria antibodies from previously infected Tanzanian donors was also analysed....
This podcast gives an overview of malaria, including prevention and treatment, and what CDC is doing to help control and prevent malaria globally. Created: 4/18/2008 by National Center for Zoonotic, Vector-Borne, and Enteric Diseases (NCZVED). Date Released: 4/18/2008.
Wanji, Samuel; Kengne-Ouafo, Arnaud J; Eyong, Ebanga E Joan; Kimbi, Helen K; Tendongfor, Nicholas; Ndamukong-Nyanga, Judith L; Nana-Djeunga, Hugues C; Bourguinat, Catherine; Sofeu-Feugaing, David D; Charvet, Claude L
The present study analyzed the relationship between the genetic diversity of Plasmodium falciparum and parasitologic/entomologic indices in the Mount Cameroon region by using merozoite surface protein 1 as a genetic marker. Blood samples were collected from asymptomatic children from three altitude zones (high, intermediate, and low). Parasitologic and entomologic indices were determined by microscopy and landing catch mosquito collection/circumsporozoite protein-enzyme-linked immunosorbent assay, respectively. A total of 142 randomly selected P. falciparum-positive blood samples were genotyped by using a nested polymerase chain reaction-based technique. K-1 polymerase chain reaction products were also sequenced. As opposed to high altitude, the highest malaria prevalence (70.65%) and entomologic inoculation rate (2.43 infective/bites/night) were recorded at a low altitude site. Seven (18.91%), 22 (36.66%), and 19 (42.22%) samples from high, intermediate, and low altitudes, respectively, contained multiclonal infections. A new K-1 polymorphism was identified. This study shows a positive non-linear association between low/intermediate altitude (high malaria transmission) and an increase in P. falciparum merozoite surface protein 1 block 2 polymorphisms.
Full Text Available Abstract Background In clinical trials, immunopotentiating reconstituted influenza virosomes (IRIVs have shown great potential as a versatile antigen delivery platform for synthetic peptides derived from Plasmodium falciparum antigens. This study describes the immunogenicity of a virosomally-formulated recombinant fusion protein comprising domains of the two malaria vaccine candidate antigens MSP3 and GLURP. Methods The highly purified recombinant protein GMZ2 was coupled to phosphatidylethanolamine and the conjugates incorporated into the membrane of IRIVs. The immunogenicity of this adjuvant-free virosomal formulation was compared to GMZ2 formulated with the adjuvants Montanide ISA 720 and Alum in three mouse strains with different genetic backgrounds. Results Intramuscular injections of all three candidate vaccine formulations induced GMZ2-specific antibody responses in all mice tested. In general, the humoral immune response in outbred NMRI mice was stronger than that in inbred BALB/c and C57BL/6 mice. ELISA with the recombinant antigens demonstrated immunodominance of the GLURP component over the MSP3 component. However, compared to the Al(OH3-adjuvanted formulation the two other formulations elicited in NMRI mice a larger proportion of anti-MSP3 antibodies. Analyses of the induced GMZ2-specific IgG subclass profiles showed for all three formulations a predominance of the IgG1 isotype. Immune sera against all three formulations exhibited cross-reactivity with in vitro cultivated blood-stage parasites. Immunofluorescence and immunoblot competition experiments showed that both components of the hybrid protein induced IgG cross-reactive with the corresponding native proteins. Conclusion A virosomal formulation of the chimeric protein GMZ2 induced P. falciparum blood stage parasite cross-reactive IgG responses specific for both MSP3 and GLURP. GMZ2 thus represents a candidate component suitable for inclusion into a multi-valent virosomal
Crompton, Peter D; Pierce, Susan K; Miller, Louis H
Malaria caused by Plasmodium falciparum remains a major public health threat, especially among children and pregnant women in Africa. An effective malaria vaccine would be a valuable tool to reduce the disease burden and could contribute to elimination of malaria in some regions of the world. Current malaria vaccine candidates are directed against human and mosquito stages of the parasite life cycle, but thus far, relatively few proteins have been studied for potential vaccine development. The most advanced vaccine candidate, RTS,S, conferred partial protection against malaria in phase II clinical trials and is currently being evaluated in a phase III trial in Africa. New vaccine targets need to be identified to improve the chances of developing a highly effective malaria vaccine. A better understanding of the mechanisms of naturally acquired immunity to malaria may lead to insights for vaccine development.
Full Text Available Abstract Background The Plasmodium falciparum chimeric protein PfCP-2.9 is a promising asexual-stage malaria vaccine evaluated in clinical trials. This chimeric protein consists of two cysteine-rich domains: domain III of the apical membrane antigen 1 (AMA-1 [III] and the C-terminal region of the merozoite surface protein 1 (MSP1-19. It has been reported that the fusion of these two antigens enhanced their immunogenicity and antibody-mediated inhibition of parasite growth in vitro. Methods The 15N-labeled and 13C/15N-labeled PfCP-2.9 was produced in Pichia pastoris for nuclear magnetic resonance (NMR structure analysis. The chemical shift assignments of PfCP-2.9 were compared with those previously reported for the individual domains (i.e., PfAMA-1(III or PfMSP 1-19. The two-dimensional spectra and transverse relaxation rates (R2 of the PfMSP1-19 alone were compared with that of the PfCP-2.9. Results Confident backbone assignments were obtained for 122 out of 241 residues of PfCP-2.9. The assigned residues in PfCP-2.9 were very similar to those previously reported for the individual domains. The conformation of the PfMSP1-19 in different constructs is essentially the same. Comparison of transverse relaxation rates (R2 strongly suggests no weak interaction between the domains. Conclusions These data indicate that the fusion of AMA-1(III and MSP1-19 as chimeric protein did not change their structures, supporting the use of the chimeric protein as a potential malaria vaccine.
Dara, Antoine; Drábek, Elliott F; Travassos, Mark A; Moser, Kara A; Delcher, Arthur L; Su, Qi; Hostelley, Timothy; Coulibaly, Drissa; Daou, Modibo; Dembele, Ahmadou; Diarra, Issa; Kone, Abdoulaye K; Kouriba, Bourema; Laurens, Matthew B; Niangaly, Amadou; Traore, Karim; Tolo, Youssouf; Fraser, Claire M; Thera, Mahamadou A; Djimde, Abdoulaye A; Doumbo, Ogobara K; Plowe, Christopher V; Silva, Joana C
Encoded by the var gene family, highly variable Plasmodium falciparum erythrocyte membrane protein-1 (PfEMP1) proteins mediate tissue-specific cytoadherence of infected erythrocytes, resulting in immune evasion and severe malaria disease. Sequencing and assembling the 40-60 var gene complement for individual infections has been notoriously difficult, impeding molecular epidemiological studies and the assessment of particular var elements as subunit vaccine candidates. We developed and validated a novel algorithm, Exon-Targeted Hybrid Assembly (ETHA), to perform targeted assembly of var gene sequences, based on a combination of Pacific Biosciences and Illumina data. Using ETHA, we characterized the repertoire of var genes in 12 samples from uncomplicated malaria infections in children from a single Malian village and showed them to be as genetically diverse as vars from isolates from around the globe. The gene var2csa, a member of the var family associated with placental malaria pathogenesis, was present in each genome, as were vars previously associated with severe malaria. ETHA, a tool to discover novel var sequences from clinical samples, will aid the understanding of malaria pathogenesis and inform the design of malaria vaccines based on PfEMP1. ETHA is available at: https://sourceforge.net/projects/etha/ .
Full Text Available Abstract Background The PFD1235w Plasmodium falciparum erythrocyte membrane protein 1 (PfEMP1 antigen is associated with severe malaria in children and can be expressed on the surface of infected erythrocytes (IE adhering to ICAM1. However, the exact three-dimensional structure of this PfEMP1 and its surface-exposed epitopes are unknown. An insect cell and Escherichia coli based system was used to express single and double domains encoded by the pfd1235w var gene. The resulting recombinant proteins have been evaluated for yield and purity and their ability to induce rat antibodies, which react with the native PFD1235w PfEMP1 antigen expressed on 3D7PFD1235w-IE. Their recognition by human anti-malaria antibodies from previously infected Tanzanian donors was also analysed. Methods The recombinant proteins were run on SDS-PAGE and Western blots for quantification and size estimation. Insect cell and E. coli-produced recombinant proteins were coupled to a bead-based Luminex assay to measure the plasma antibody reactivity of 180 samples collected from Tanzanian individuals. The recombinant proteins used for immunization of rats and antisera were also tested by flow cytometry for their ability to surface label 3D7PFD1235w-IE. Results All seven pAcGP67A constructs were successfully expressed as recombinant protein in baculovirus-infected insect cells and subsequently produced to a purity of 60-97% and a yield of 2-15 mg/L. By comparison, only three of seven pET101/D-TOPO constructs expressed in the E. coli system could be produced at all with purity and yield ranging from 3-95% and 6-11 mg/L. All seven insect cell, but only two of the E. coli produced proteins induced antibodies reactive with native PFD1235w expressed on 3D7PFD1235w-IE. The recombinant proteins were recognized in an age- and transmission intensity-dependent manner by antibodies from 180 Tanzanian individuals in a bead-based Luminex assay. Conclusions The baculovirus based insect cell
Malaria D:lay still be contracted despite good cOD:lpliance with ... true that prophylaxis is always better than no prophy- laxis, nor is ... If used during pregnancy, a folic acid supplement ... include folate deficiency, agranulocytosis, illegaloblastic.
Winstanley, Peter; Ward, Stephen
Most malaria control strategies today depend on safe and effective drugs, as they have done for decades. But sensitivity to chloroquine, hitherto the workhorse of malaria chemotherapy, has rapidly declined throughout the tropics since the 1980s, and this drug is now useless in many high-transmission areas. New options for resource-constrained governments are few, and there is growing evidence that the burden from malaria has been increasing, as has malaria mortality in Africa. In this chapter, we have tried to outline the main pharmacological properties of current drugs, and their therapeutic uses and limitations. We have summarised the ways in which these drugs are employed, both in the formal health sector and in self-medication. We have briefly touched on the limitations of current drug development, but have tried to pick out a few promising drugs that are under development. Given that Plasmodium falciparum is the organism that kills, and that has developed multi-drug resistance, we have tended to focus upon it. Similarly, given that around 90% of global mortality from malaria occurs in Africa, there is the tendency to dwell on this continent. We give no apology for placing our emphasis upon the use of antimalarial drugs in endemic populations rather than their use for prophylaxis in travellers.
Full Text Available Abstract Background The Anopheles gambiae gSG6 is an anopheline-specific salivary protein which helps female mosquitoes to efficiently feed on blood. Besides its role in haematophagy, gSG6 is immunogenic and elicits in exposed individuals an IgG response, which may be used as indicator of exposure to the main African malaria vector A. gambiae. However, malaria transmission in tropical Africa is sustained by three main vectors (A. gambiae, Anopheles arabiensis and Anopheles funestus and a general marker, reflecting exposure to at least these three species, would be especially valuable. The SG6 protein is highly conserved within the A. gambiae species complex whereas the A. funestus homologue, fSG6, is more divergent (80% identity with gSG6. The aim of this study was to evaluate cross-reactivity of human sera to gSG6 and fSG6. Methods The A. funestus SG6 protein was expressed/purified and the humoral response to gSG6, fSG6 and a combination of the two antigens was compared in a population from a malaria hyperendemic area of Burkina Faso where both vectors were present, although with a large A. gambiae prevalence (>75%. Sera collected at the beginning and at the end of the high transmission/rainy season, as well as during the following low transmission/dry season, were analysed. Results According to previous observations, both anti-SG6 IgG level and prevalence decreased during the low transmission/dry season and showed a typical age-dependent pattern. No significant difference in the response to the two antigens was found, although their combined use yielded in most cases higher IgG level. Conclusions Comparative analysis of gSG6 and fSG6 immunogenicity to humans suggests the occurrence of a wide cross-reactivity, even though the two proteins carry species-specific epitopes. This study supports the use of gSG6 as reliable indicator of exposure to the three main African malaria vectors, a marker which may be useful to monitor malaria transmission
Nogueira, Paulo Afonso; Piovesan Alves, Fabiana; Fernandez-Becerra, Carmen; Pein, Oliver; Rodrigues Santos, Neida; Pereira da Silva, Luiz Hildebrando; Plessman Camargo, Erney; del Portillo, Hernando A.
Progress towards the development of a malaria vaccine against Plasmodium vivax, the most widely distributed human malaria parasite, will require a better understanding of the immune responses that confer clinical protection to patients in regions where malaria is endemic. The occurrence of clinical protection in P. vivax malaria in Brazil was first reported among residents of the riverine community of Portuchuelo, in Rondônia, western Amazon. We thus analyzed immune sera from this same human population to determine if naturally acquired humoral immune responses against the merozoite surface protein 1 of P. vivax, PvMSP1, could be associated with reduced risk of infection and/or clinical protection. Our results demonstrated that this association could be established with anti-PvMSP1 antibodies predominantly of the immunoglobulin G3 subclass directed against the N terminus but not against the C terminus, in spite of the latter being more immunogenic and capable of natural boosting. This is the first report of a prospective study of P. vivax malaria demonstrating an association of reduced risk of infection and clinical protection with antibodies against an antigen of this parasite. PMID:16622209
Lương, Khanh Vinh Quốc; Nguyễn, Lan Thi Hoàng
An abnormal calcium-parathyroid hormone (PTH)-vitamin D axis has been reported in patients with malaria infection. A role for vitamin D in malaria has been suggested by many studies. Genetic studies have identified numerous factors that link vitamin D to malaria, including human leukocyte antigen genes, toll-like receptors, heme oxygenase-1, angiopoietin-2, cytotoxic T lymphocyte antigen-4, nucleotide-binding oligomerization domain-like receptors, and Bcl-2. Vitamin D has also been implicated in malaria via its effects on the Bacillus Calmette-Guerin (BCG) vaccine, matrix metalloproteinases, mitogen-activated protein kinase pathways, prostaglandins, reactive oxidative species, and nitric oxide synthase. Vitamin D may be important in malaria; therefore, additional research on its role in malaria is needed.
Full Text Available BACKGROUND: The P. falciparum chimeric protein 2.9 (PfCP-2.9 consisting of the sequences of MSP1-19 and AMA-1 (III is a malaria vaccine candidate that was found to induce inhibitory antibodies in rabbits and monkeys. This was a phase I randomized, single-blind, placebo-controlled, dose-escalation study to evaluate the safety and immunogenicity of the PfCP-2.9 formulated with a novel adjuvant Montanide ISA720. Fifty-two subjects were randomly assigned to 4 dose groups of 10 participants, each receiving the test vaccine of 20, 50, 100, or 200 microg respectively, and 1 placebo group of 12 participants receiving the adjuvant only. METHODS AND FINDINGS: The vaccine formulation was shown to be safe and well-tolerated, and none of the participants withdrew. The total incidence of local adverse events (AEs was 75%, distributed among 58% of the placebo group and 80% of those vaccinated. Among the vaccinated, 65% had events that were mild and 15% experienced moderate AEs. Almost all systemic adverse reactions observed in this study were graded as mild and required no therapy. The participants receiving the test vaccine developed detectable antibody responses which were boosted by the repeated vaccinations. Sixty percent of the vaccinated participants had high ELISA titers (>1:10,000 of antigen-specific antibodies which could also recognize native parasite proteins in an immunofluorescence assay (IFA. CONCLUSION: This study is the first clinical trial for this candidate and builds on previous investigations supporting PfCP-2.9/ISA720 as a promising blood-stage malaria vaccine. Results demonstrate safety, tolerability (particularly at the lower doses tested and immunogenicity of the formulation. Further clinical development is ongoing to explore optimizing the dose and schedule of the formulation to decrease reactogenicity without compromising immunogenicity. TRIAL REGISTRATION: Chinese State Food and Drug Administration (SFDA 2002SL0046; Controlled
Requena, Pilar; Rui, Edmilson; Padilla, Norma; Martínez-Espinosa, Flor E; Castellanos, Maria Eugenia; Bôtto-Menezes, Camila; Malheiro, Adriana; Arévalo-Herrera, Myriam; Kochar, Swati; Kochar, Sanjay K; Kochar, Dhanpat K; Umbers, Alexandra J; Ome-Kaius, Maria; Wangnapi, Regina; Hans, Dhiraj; Menegon, Michela; Mateo, Francesca; Sanz, Sergi; Desai, Meghna; Mayor, Alfredo; Chitnis, Chetan C; Bardají, Azucena; Mueller, Ivo; Rogerson, Stephen; Severini, Carlo; Fernández-Becerra, Carmen; Menéndez, Clara; Del Portillo, Hernando; Dobaño, Carlota
P. vivax infection during pregnancy has been associated with poor outcomes such as anemia, low birth weight and congenital malaria, thus representing an important global health problem. However, no vaccine is currently available for its prevention. Vir genes were the first putative virulent factors associated with P. vivax infections, yet very few studies have examined their potential role as targets of immunity. We investigated the immunogenic properties of five VIR proteins and two long synthetic peptides containing conserved VIR sequences (PvLP1 and PvLP2) in the context of the PregVax cohort study including women from five malaria endemic countries: Brazil, Colombia, Guatemala, India and Papua New Guinea (PNG) at different timepoints during and after pregnancy. Antibody responses against all antigens were detected in all populations, with PNG women presenting the highest levels overall. P. vivax infection at sample collection time was positively associated with antibody levels against PvLP1 (fold-increase: 1.60 at recruitment -first antenatal visit-) and PvLP2 (fold-increase: 1.63 at delivery), and P. falciparum co-infection was found to increase those responses (for PvLP1 at recruitment, fold-increase: 2.25). Levels of IgG against two VIR proteins at delivery were associated with higher birth weight (27 g increase per duplicating antibody levels, ppregnant women had significantly higher antigen-specific IFN-γ TH1 responses (p=0.006) and secreted less pro-inflammatory cytokines TNF and IL-6 after PvLP2 stimulation than P. vivax-infected women (p<0.05). These data demonstrate that VIR antigens induce the natural acquisition of antibody and T cell memory responses that might be important in immunity to P. vivax during pregnancy in very diverse geographical settings.
Variation in the immune responses against Plasmodium falciparum merozoite surface protein-1 and apical membrane antigen-1 in children residing in the different epidemiological strata of malaria in Cameroon.
Kwenti, Tebit Emmanuel; Moye, Adzemye Linus; Wiylanyuy, Adzemye Basil; Njunda, Longdoh Anna; Nkuo-Akenji, Theresa
Studies to assess the immune responses against malaria in Cameroonian children are limited. The purpose of this study was to assess the immune responses against Plasmodium falciparum merozoite surface protein-1 (MSP-1 19 ) and apical membrane antigen-1 (AMA-1) in children residing in the different epidemiological strata of malaria in Cameroon. In a cross-sectional survey performed between April and July 2015, 602 children between 2 and 15 years (mean ± SD = 5.7 ± 3.7), comprising 319 (53%) males were enrolled from five epidemiological strata of malaria in Cameroon including: the sudano-sahelian (SS) strata, the high inland plateau (HIP) strata, the south Cameroonian equatorial forest (SCEF) strata, the high western plateau (HWP) strata, and the coastal (C) strata. The children were screened for clinical malaria (defined by malaria parasitaemia ≥ 5000 parasites/µl plus axillary temperature ≥ 37.5 °C). Their antibody responses were measured against P. falciparum MSP-1 19 and AMA-1 vaccine candidate antigens using standard ELISA technique. A majority of the participants were IgG responders 72.1% (95% CI 68.3-75.6). The proportion of responders was higher in females (p = 0.002) and in children aged 10 years and above (p = 0.005). The proportion of responders was highest in Limbe (C strata) and lowest in Ngaoundere (HIP strata) (p malaria (p malaria parasites. The immune responses varied considerably across the different strata: the highest levels observed in the C strata and the lowest in the HIP strata. Furthermore, malaria transmission in Cameroon could be categorized into two major groups based on the serological reaction of the children: the southern (comprising C and SCEF strata) and northern (comprising HWP, HIP and SS strata) groups. These findings may have significant implications in the design of future trials for evaluating malaria vaccine candidates in Cameroon.
Rønn, A M; Bygbjerg, Ib Christian; Jacobsen, E
An increasing number of cases of malaria, imported to Denmark, are caused by Plasmodium falciparum and severe and complicated cases are more often seen. In the Department of Infectious Diseases, Rigshospitalet, 23 out of 32 cases, hospitalized from 1.1-30.6.1988, i.e. 72%, were caused by P...
Full Text Available Apicomplexan parasites are obligate intracellular parasites that infect a variety of hosts, causing significant diseases in livestock and humans. The invasive forms of the parasites invade their host cells by gliding motility, an active process driven by parasite adhesion proteins and molecular motors. A crucial point during host cell invasion is the formation of a ring-shaped area of intimate contact between the parasite and the host known as a tight junction. As the invasive zoite propels itself into the host-cell, the junction moves down the length of the parasite. This process must be tightly regulated and signalling is likely to play a role in this event. One crucial protein for tight-junction formation is the apical membrane antigen 1 (AMA1. Here we have investigated the phosphorylation status of this key player in the invasion process in the human malaria parasite Plasmodium falciparum. We show that the cytoplasmic tail of P. falciparum AMA1 is phosphorylated at serine 610. We provide evidence that the enzyme responsible for serine 610 phosphorylation is the cAMP regulated protein kinase A (PfPKA. Importantly, mutation of AMA1 serine 610 to alanine abrogates phosphorylation of AMA1 in vivo and dramatically impedes invasion. In addition to shedding unexpected new light on AMA1 function, this work represents the first time PKA has been implicated in merozoite invasion.
Luis Andre Mariuba
Full Text Available Rhoptry-associated protein 2 (RAP2 is known to be discharged from rhoptry onto the membrane surface of infected and uninfected erythrocytes (UEs ex vivo and in vitro and this information provides new insights into the understanding of the pathology of severe anemia in falciparum malaria. In this study, a hexahistidine-tagged recombinant protein corresponding to residues 5-190 of the N-terminal of Plasmodium falciparum RAP2 (rN-RAP2 was produced using a new method of solubilization and purification. Expression was induced with D-lactose, a less expensive alternative inducer to the more common isopropyl-²-D-thio-galactopyranosidase. The recombinant protein was purified using two types of commercially-available affinity columns, iminodiacetic and nitrilotriacetic. rN-RAP2 had immunogenic potential, since it induced high titers of anti-RAP2 antibodies in mice. These antibodies recognized full-length RAP2 prepared from Triton X-100 extracts from two strains of P. falciparum. In fact, the antibody recognized a 29-kDa product of RAP2 cleavage as well as 82 and 70-kDa products of RAP1 cleavage. These results indicate that the two antigens share sequence epitopes. Our expressed protein fragment was shown to contain a functional epitope that is also present in rhoptry-derived ring surface protein 2 which attaches to the surface of both infected and UEs and erythroid precursor cells in the bone marrow of malaria patients. Serum from malaria patients who developed anemia during infection recognized rN-RAP2, suggesting that this protein fragment may be important for epidemiological studies investigating whether immune responses to RAP2 exacerbate hemolysis in falciparum malaria patients.
Malaria is a serious mosquito-borne disease that can lead to death. This podcast discusses malaria risk when traveling to tropical areas, as well as how to protect yourself and your family from malaria infection.
Gjørup, Ida E; Vestergaard, Lasse S; Møller, Kirsten
When travellers return from malaria-endemic areas and present to hospital with fever, microscopy of blood smears remains the leading method to verify a suspected diagnosis of malaria. Additional laboratory abnormalities may, however, also be indicative of acute malaria infection. We monitored....... For comparison, admission values of a group of febrile patients with suspected malaria, but with negative blood slides, were also assessed (n=66). The thrombocyte, leucocyte counts and coagulation factor II-VII-X were significantly lower in the malaria group compared to the non-malaria group, whereas the C......-reactive protein, lactate dehydrogenase and bilirubin were significantly higher in the malaria group. The differences were particularly strong with falciparum malaria. By contrast, haemoglobin levels were not affected. In conclusion, our study emphasizes the role of a few commonly analysed laboratory parameters...
Expression, Purification and Characterization of GMZ2'.10C, a Complex Disulphide-Bonded Fusion Protein Vaccine Candidate against the Asexual and Sexual Life-Stages of the Malaria-Causing Plasmodium falciparum Parasite
Mistarz, Ulrik H; Singh, Susheel K; Nguyen, Tam T T N
PURPOSE: Production and characterization of a chimeric fusion protein (GMZ2'.10C) which combines epitopes of key malaria parasite antigens: glutamate-rich protein (GLURP), merozoite surface protein 3 (MSP3), and the highly disulphide bonded Pfs48/45 (10C). GMZ2'.10C is a potential candidate...... was analysed by RP-HPLC, SEC-HPLC, 2-site ELISA, gel-electrophoresis and Western blotting. Structural characterization (mass analysis, peptide mapping and cysteine connectivity mapping) was performed by LC-MS/MS. RESULTS: CP-GMZ2'.10C resulted in similar purity, yield, structure and stability as compared to IP...
Vignali, Marissa; Armour, Christopher D.; Chen, Jingyang; Morrison, Robert; Castle, John C.; Biery, Matthew C.; Bouzek, Heather; Moon, Wonjong; Babak, Tomas; Fried, Michal; Raymond, Christopher K.; Duffy, Patrick E.
Malaria caused by Plasmodium falciparum results in approximately 1 million annual deaths worldwide, with young children and pregnant mothers at highest risk. Disease severity might be related to parasite virulence factors, but expression profiling studies of parasites to test this hypothesis have been hindered by extensive sequence variation in putative virulence genes and a preponderance of host RNA in clinical samples. We report here the application of RNA sequencing to clinical isolates of P. falciparum, using not-so-random (NSR) primers to successfully exclude human ribosomal RNA and globin transcripts and enrich for parasite transcripts. Using NSR-seq, we confirmed earlier microarray studies showing upregulation of a distinct subset of genes in parasites infecting pregnant women, including that encoding the well-established pregnancy malaria vaccine candidate var2csa. We also describe a subset of parasite transcripts that distinguished parasites infecting children from those infecting pregnant women and confirmed this observation using quantitative real-time PCR and mass spectrometry proteomic analyses. Based on their putative functional properties, we propose that these proteins could have a role in childhood malaria pathogenesis. Our study provides proof of principle that NSR-seq represents an approach that can be used to study clinical isolates of parasites causing severe malaria syndromes as well other blood-borne pathogens and blood-related diseases. PMID:21317536
Vignali, Marissa; Armour, Christopher D; Chen, Jingyang; Morrison, Robert; Castle, John C; Biery, Matthew C; Bouzek, Heather; Moon, Wonjong; Babak, Tomas; Fried, Michal; Raymond, Christopher K; Duffy, Patrick E
Malaria caused by Plasmodium falciparum results in approximately 1 million annual deaths worldwide, with young children and pregnant mothers at highest risk. Disease severity might be related to parasite virulence factors, but expression profiling studies of parasites to test this hypothesis have been hindered by extensive sequence variation in putative virulence genes and a preponderance of host RNA in clinical samples. We report here the application of RNA sequencing to clinical isolates of P. falciparum, using not-so-random (NSR) primers to successfully exclude human ribosomal RNA and globin transcripts and enrich for parasite transcripts. Using NSR-seq, we confirmed earlier microarray studies showing upregulation of a distinct subset of genes in parasites infecting pregnant women, including that encoding the well-established pregnancy malaria vaccine candidate var2csa. We also describe a subset of parasite transcripts that distinguished parasites infecting children from those infecting pregnant women and confirmed this observation using quantitative real-time PCR and mass spectrometry proteomic analyses. Based on their putative functional properties, we propose that these proteins could have a role in childhood malaria pathogenesis. Our study provides proof of principle that NSR-seq represents an approach that can be used to study clinical isolates of parasites causing severe malaria syndromes as well other blood-borne pathogens and blood-related diseases.
Rieger, Harden; Yoshikawa, Hiroshi Y; Quadt, Katharina
Infections with the human malaria parasite Plasmodium falciparum during pregnancy can lead to severe complications for both mother and child, resulting from the cytoadhesion of parasitized erythrocytes in the intervillous space of the placenta. Cytoadherence is conferred by the specific interacti...... was cooperative and shear stress induced. These findings suggest that the CSA density, together with allosteric effects in VAR2CSA, aid in discriminating between different CSA milieus....
Hviid, Lars; Jensen, Anja T R
to be a central element in the pathogenesis of the disease. It is mediated by the interaction of parasite ligands on the erythrocyte surface and a range of host receptor molecules in many organs and tissues. Among several proteins and protein families implicated in this process, the P. falciparum erythrocyte...... membrane protein 1 (PfEMP1) family of high-molecular weight and highly variable antigens appears to be the most prominent. In this chapter, we aim to provide a systematic overview of the current knowledge about these proteins, their structure, their function, how they are presented on the erythrocyte...
3D7-derived Plasmodium falciparum erythrocyte membrane protein 1 is a frequent target of naturally acquired antibodies recognizing protein domains in a particular pattern independent of malaria transmission intensity
Joergensen, Louise; Vestergaard, Lasse S; Turner, Louise
Protection against Plasmodium falciparum malaria is largely mediated by IgG against surface Ags such as the erythrocyte membrane protein 1 family (PfEMP1) responsible for antigenic variation and sequestration of infected erythrocytes. PfEMP1 molecules can be divided into groups A, B/A, B, C, and B......, the sequence by which individuals acquired Abs to particular constructs was largely the same in the three villages. This indicates that the pattern of PfEMP1 expression by parasites transmitted at the different sites was similar, suggesting that PfEMP1 expression is nonrandom and shaped by host......-parasite relationship factors operating at all transmission intensities....
Cellular responses to Plasmodium falciparum erythrocyte membrane protein-1: use of relatively conserved synthetic peptide pools to determine CD4 T cell responses in malaria-exposed individuals in Benin, West Africa
Full Text Available Abstract Background Plasmodium falciparum erythrocyte membrane protein-1, a variant antigen of the malaria parasite, is potentially a target for the immune response. It would be important to determine whether there are CD4 T cells that recognise conserved regions. However, within the relatively conserved region, there is variation. It is not possible to test T cell responses from small field samples with all possible peptides. Methods We have aligned sequences that are relatively conserved between several PfEMP1 molecules, and chosen a representative sequence similar to most of the PfEMP1 variants. Using these peptides as pools representing CIDRα, CIDRβ and DBLβ-δ domains, DBLα domain, and EXON 2 domain of PfEMP1, we measured the CD4 T cell responses of malaria-exposed donors from Benin, West Africa by a FACS based assay. Results All the three peptide pools elicited a CD4 T cell response in a proportion of malaria-exposed and non-exposed donors. CD4 T cell proliferation occurs at a relatively higher magnitude to peptide pools from the DBLα and EXON 2 in the malaria-exposed donors living in Benin than in the UK malaria-unexposed donors. Conclusions These findings suggest that an immunological recall response to conserved peptides of a variant antigen can be measured. Further testing of individual peptides in a positive pool will allow us to determine those conserved sequences recognised by many individuals. These types of assays may provide information on conserved peptides of PfEMP1 which could be useful for stimulating T cells to provide help to P. falciparum specific B cells.
Full Text Available Abstract Background GIMAP (GTPase of the immunity-associated protein family proteins are a family of putative GTPases believed to be regulators of cell death in lymphomyeloid cells. GIMAP1 was the first reported member of this gene family, identified as a gene up-regulated at the RNA level in the spleens of mice infected with the malarial parasite, Plasmodium chabaudi. Methods A monoclonal antibody against mouse GIMAP1 was developed and was used to analyse the expression of the endogenous protein in tissues of normal mice and in defined sub-populations of cells prepared from lymphoid tissues using flow cytometry. It was also used to assess the expression of GIMAP1 protein after infection and/or immunization of mice with P. chabaudi. Real-time PCR analysis was employed to measure the expression of GIMAP1 for comparison with the protein level analysis. Results GIMAP1 protein expression was detected in all lineages of lymphocytes (T, B, NK, in F4/80+ splenic macrophages and in some lymphoid cell lines. Additional evidence is presented suggesting that the strong expression by mature B cells of GIMAP1 and other GIMAP genes and proteins seen in mice may be a species-dependent characteristic. Unexpectedly, no increase was found in the expression of GIMAP1 in P. chabaudi infected mice at either the mRNA or protein level, and this remained so despite applying a number of variations to the protocol. Conclusion The model of up-regulation of GIMAP1 in response to infection/immunization with P. chabaudi is not a robustly reproducible experimental system. The GIMAP1 protein is widely expressed in lymphoid cells, with an interesting increase in expression in the later stages of B cell development. Alternative approaches will be required to define the functional role of this GTPase in immune cells.
Full Text Available Malaria infected erythrocytes show increased permeability to a number of solutes important for parasite growth as mediated by the Plasmodial Surface Anion Channel (PSAC. The P. falciparum clag3 genes have recently been identified as key determinants of PSAC, though exactly how they contribute to channel function and whether additional host/parasite proteins are required remain unknown. To begin to answer these questions, I have taken a biochemical approach. Here I have used an epitope-tagged CLAG3 parasite to perform co-immunoprecipitation experiments using membrane fractions of infected erythrocytes. Native PAGE and mass spectrometry studies reveal that CLAG3 participate in at least three different high molecular weight complexes: a ~720kDa complex consisting of CLAG3, RHOPH2 and RHOPH3; a ~620kDa complex consisting of CLAG3 and RHOPH2; and a ~480kDa complex composed solely of CLAG3. Importantly, these complexes can be found throughout the parasite lifecycle but are absent in untransfected controls. Extracellular biotin labeling and protease susceptibility studies localize the 480kDa complex to the erythrocyte membrane. This complex, likely composed of a homo-oligomer of 160kDa CLAG3, may represent a functional subunit, possibly the pore, of PSAC.
Full Text Available Abstract Background The malarial parasite, Plasmodium falciparum (Pf, is responsible for nearly 2 million deaths worldwide. However, the mechanisms of cellular signaling in the parasite remain largely unknown. Recent discovery of a few protein kinases and phosphatases point to a thriving reversible phosphorylation system in the parasite, although their function and regulation need to be determined. Results We provide biochemical and sequence evidence for a protein serine/threonine phosphatase type PP5 in Plasmodium falciparum, and named it PfPP5. The 594-amino acid polypeptide was encoded by a 1785 nucleotide long intronless gene in the parasite. The recombinant protein, expressed in bacteria, was indistinguishable from native PfPP5. Sequencing comparison indicated that the extra-long N-terminus of PfPP5 outside the catalytic core contained four tetratricopeptide repeats (TPRs, compared to three such repeats in other PP5 phosphatases. The PfPP5 N-terminus was required for stimulation of the phosphatase activity by polyunsaturated fatty acids. Co-immunoprecipitation demonstrated an interaction between native PfPP5 and Pf heat shock protein 90 (hsp90. PfPP5 was expressed in all the asexual erythrocytic stages of the parasite, and was moderately sensitive to okadaic acid. Conclusions This is the first example of a TPR-domain protein in the Apicomplexa family of parasites. Since TPR domains play important roles in protein-protein interaction, especially relevant to the regulation of PP5 phosphatases, PfPP5 is destined to have a definitive role in parasitic growth and signaling pathways. This is exemplified by the interaction between PfPP5 and the cognate chaperone hsp90.
He, Xiu; He, Zheng-Bo; Zhang, Yu-Juan; Zhou, Yong; Xian, Peng-Jie; Qiao, Liang; Chen, Bin
Anopheles sinensis is a major malaria vector. Insect odorant-binding proteins (OBPs) may function in the reception of odorants in the olfactory system. The classification and characterization of the An. sinensis OBP genes have not been systematically studied. In this study, 64 putative OBP genes were identified at the whole-genome level of An. sinensis based on the comparison between OBP conserved motifs, PBP_GOBP, and phylogenetic analysis with An. gambiae OBPs. The characterization of An. sinensis OBPs, including the motif's conservation, gene structure, genomic organization and classification, were investigated. A new gene, AsOBP73, belonging to the Plus-C subfamily, was identified with the support of transcript and conservative motifs. These An. sinensis OBP genes were classified into three subfamilies with 37, 15 and 12 genes in the subfamily Classic, Atypical and Plus-C, respectively. The genomic organization of An. sinensis OBPs suggests a clustered distribution across nine different scaffolds. Eight genes (OBP23-28, OBP63-64) might originate from a single gene through a series of historic duplication events at least before divergence of Anopheles, Culex and Aedes. The microsynteny analyses indicate a very high synteny between An. sinensis and An. gambiae OBPs. OBP70 and OBP71 earlier classified under Plus-C in An. gambiae are recognized as belonging to the group Obp59a of the Classic subfamily, and OBP69 earlier classified under Plus-C has been moved to the Atypical subfamily in this study. The study established a basic information frame for further study of the OBP genes in insects as well as in An. sinensis. © 2016 Institute of Zoology, Chinese Academy of Sciences.
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Full Text Available AbstrakMalaria masih merupakan masalah kesehatan masyarakat dunia. Berdasarkan klasifikasi klinis, malaria dibedakan atas malaria berat dan malaria tanpa komplikasi. Malaria serebral merupakan komplikasi terberat dari malaria falsiparum.Telah dilakukan penelitian seksi silang terhadap penderita malaria falciparum yang dirawat inap di Bangsal Penyakit Dalam RS. Perjan. Dr. M. Djamil Padang dari bulan Juni 2002 sampai Juni 2006. Pada penelitian ini didapatkan jumlah sampel sebanyak 60 orang, terdiri dari 16 orang penderita malaria serebral dan 44 orang penderita malaria tanpa komplikasi.Data penelitian menunjukan terdapat perbedaan bermakna nilai hematokrit (p<0,05 dan jumlah leukosit (p<0,05 antara penderita malaria serebral dengan penderita malaria tanpa komplikasi. Dan terdapat korelasi positif antara nilai hemoglobin dengan hematokrit (r=0,864; p<0,05 pada penderita malaria falsiparum.Kata kunci: malaria serebral, malaria tanpa komplikasi, malaria falsiparumAbstract Malaria is still a problem of health of world society. Based on the clinical classification, are distinguished on severe malaria and uncomplicated malaria. Cerebral malaria is the worst complication of falciparum malaria. Cross section of the research done at the Hospital Dr. M. Djamil Padang againts medical record of malaria patients who are hospitalized in the Internal Medicine from June 2002 until June 2004. In this study, a total sample of 60 people, consisting of 16 cerebral malaria and 44 uncomplicated malaria. Data showed there were significant differences for hematocrit values (p <0.05 and total leukocytes values (p <0.05 between cerebral malaria and uncomplicated malaria patients. There is a positive correlation between hemoglobin with hematocrit values (r = 0.864; p <0.05 of falciparum malaria patients. Keywords: cerebral malaria, uncomplicated malaria, falciparum malaria
Sylla, Khadime; Tine, Roger Clément Kouly; Ndiaye, Magatte; Sow, Doudou; Sarr, Aïssatou; Mbuyi, Marie Louise Tshibola; Diouf, Ibrahima; Lô, Amy Colé; Abiola, Annie; Seck, Mame Cheikh; Ndiaye, Mouhamadou; Badiane, Aïda Sadikh; N'Diaye, Jean Louis A; Ndiaye, Daouda; Faye, Oumar; Dieng, Thérèse; Dieng, Yémou; Ndir, Oumar; Gaye, Oumar; Faye, Babacar
In Senegal, a significant decrease of malaria transmission intensity has been noted the last years. Parasitaemia has become lower and, therefore, more difficult to detect by microscopy. In the context of submicroscopic parasitaemia, it has become relevant to rely on relevant malaria surveillance tools to better document malaria epidemiology in such settings. Serological markers have been proposed as an essential tool for malaria surveillance. This study aimed to evaluate the sero-epidemiological situation of Plasmodium falciparum malaria in two sentinel sites in Senegal. Cross-sectional surveys were carried out in Velingara (south Senegal) and Keur Soce (central Senegal) between September and October 2010. Children under 10 years old, living in these areas, were enrolled using two-level, random sampling methods. P. falciparum infection was diagnosed using microscopy. P. falciparum antibodies against circumsporozoite protein (CSP), apical membrane protein (AMA1) and merozoite surface protein 1_42 (MSP1_42) were measured by ELISA method. A stepwise logistic regression analysis was done to assess factors associated with P. falciparum antibodies carriage. A total of 1,865 children under 10 years old were enrolled. The overall falciparum malaria prevalence was 4.99% with high prevalence in Velingara of 10.03% compared to Keur Soce of 0.3%. Symptomatic malaria cases (fever associated with parasitaemia) represented 17.37%. Seroprevalence of anti-AMA1, anti-MSP1_42 and anti-CSP antibody was 38.12, 41.55 and 40.38%, respectively. The seroprevalence was more important in Velingara and increased with age, active malaria infection and area of residence. The use of serological markers can contribute to improved malaria surveillance in areas with declining malaria transmission. This study provided useful baseline information about the sero-epidemiological situation of malaria in Senegal and can contribute to the identification of malaria hot spots in order to concentrate
Bengtsson, Dominique C; Sowa, Kordai M P; Arnot, David E
There is a need for improved methods for in situ localization of surface proteins on Plasmodium falciparum-infected erythrocytes to help understand how these antigens are trafficked to, and positioned within, the host cell membrane. This protocol for confocal immunofluorescence microscopy combines...... and permeabilization; indirect labeling of the internal antigen using a secondary antibody tagged with a spectrally distinct fluorescent dye; and detection of the differentially labeled antigens using a laser scanning confocal microscope. The protocol can be completed in approximately 7 h. Although the protocol...... surface antigen labeling on live cells with subsequent fixation and permeabilization, which enables antibodies to penetrate the cell and label internal antigens. The key steps of the protocol are as follows: indirect labeling of the surface antigen using a fluorescently tagged secondary antibody; fixation...
Dec 10, 2011 ... malaria transmission dynamics, vector biology, ecology, behaviour and ... control achieved by ITNs, as this may vary with the molecular ..... with multilocus protein electrophoresis (11.3%) and cytogenetic analysis together with PCR (2%). ... the mosquito host is one of the principal components in malaria ...
Background: Plasmodium falciparum, the most dangerous malaria parasite species to ... tigen for subunit malaria vaccine.10 It comprises highly ... were also prepared for Giemsa staining as described by ... parasites with different alleles at a given locus and ranges ..... surface protein 1, immune evasion and vaccines against.
Cohee, Lauren M; Laufer, Miriam K
Malaria is a leading cause of morbidity and mortality in endemic areas, leading to an estimated 438,000 deaths in 2015. Malaria is also an important health threat to travelers to endemic countries and should be considered in evaluation of any traveler returning from a malaria-endemic area who develops fever. Considering the diagnosis of malaria in patients with potential exposure is critical. Prompt provision of effective treatment limits the complications of malaria and can be life-saving. Understanding Plasmodium species variation, epidemiology, and drug-resistance patterns in the geographic area where infection was acquired is important for determining treatment choices. Copyright © 2017 Elsevier Inc. All rights reserved.
Hoffmann, A L; Rønn, A M; Langhoff-Roos, J
In regions where malaria is endemism, the disease is a recognised cause of complications of pregnancy such as spontaneous abortion, premature delivery, intrauterine growth retardation and foetal death. Malaria is seldom seen in pregnant women in Denmark but, during the past two years, the authors...... the patients but also their practitioners were unaware that malaria can occur several years after exposure. Three out of the four patients had employed malaria prophylaxis. As resistance to malarial prophylactics in current use is increasing steadily, chemoprophylaxis should be supplemented by mechanical...... protection against malaria and insect repellents. As a rule, malaria is treated with chloroquine. In cases of Falciparum malaria in whom chloroquine resistance is suspected, treatment with mefloquine may be employed although this should only be employed in cases of dire necessity in pregnant patients during...
Dodoo, D; Theisen, M; Kurtzhals, J A
The development of effective malaria vaccines depends on the identification of targets of well-defined protective immune responses. Data and samples from a longitudinal study of a cohort of children from coastal Ghana were used to investigate the role of antibody responses to 3 regions of the Pla...
Christopher J A Duncan
Full Text Available Inhibition of parasite growth is a major objective of blood-stage malaria vaccines. The in vitro assay of parasite growth inhibitory activity (GIA is widely used as a surrogate marker for malaria vaccine efficacy in the down-selection of candidate blood-stage vaccines. Here we report the first study to examine the relationship between in vivo Plasmodium falciparum growth rates and in vitro GIA in humans experimentally infected with blood-stage malaria.In this phase I/IIa open-label clinical trial five healthy malaria-naive volunteers were immunised with AMA1/C1-Alhydrogel+CPG 7909, and together with three unvaccinated controls were challenged by intravenous inoculation of P. falciparum infected erythrocytes.A significant correlation was observed between parasite multiplication rate in 48 hours (PMR and both vaccine-induced growth-inhibitory activity (Pearson r = -0.93 [95% CI: -1.0, -0.27] P = 0.02 and AMA1 antibody titres in the vaccine group (Pearson r = -0.93 [95% CI: -0.99, -0.25] P = 0.02. However immunisation failed to reduce overall mean PMR in the vaccine group in comparison to the controls (vaccinee 16 fold [95% CI: 12, 22], control 17 fold [CI: 0, 65] P = 0.70. Therefore no impact on pre-patent period was observed (vaccine group median 8.5 days [range 7.5-9], control group median 9 days [range 7-9].Despite the first observation in human experimental malaria infection of a significant association between vaccine-induced in vitro growth inhibitory activity and in vivo parasite multiplication rate, this did not translate into any observable clinically relevant vaccine effect in this small group of volunteers.ClinicalTrials.gov [NCT00984763].
Expression, Purification and Characterization of GMZ2'.10C, a Complex Disulphide-Bonded Fusion Protein Vaccine Candidate against the Asexual and Sexual Life-Stages of the Malaria-Causing Plasmodium falciparum Parasite.
Mistarz, Ulrik H; Singh, Susheel K; Nguyen, Tam T T N; Roeffen, Will; Yang, Fen; Lissau, Casper; Madsen, Søren M; Vrang, Astrid; Tiendrebeogo, Régis W; Kana, Ikhlaq H; Sauerwein, Robert W; Theisen, Michael; Rand, Kasper D
Production and characterization of a chimeric fusion protein (GMZ2'.10C) which combines epitopes of key malaria parasite antigens: glutamate-rich protein (GLURP), merozoite surface protein 3 (MSP3), and the highly disulphide bonded Pfs48/45 (10C). GMZ2'.10C is a potential candidate for a multi-stage malaria vaccine that targets both transmission and asexual life-cycle stages of the parasite. GMZ2'.10C was produced in Lactococcus lactis and purified using either an immunoaffinity purification (IP) or a conventional purification (CP) method. Protein purity and stability was analysed by RP-HPLC, SEC-HPLC, 2-site ELISA, gel-electrophoresis and Western blotting. Structural characterization (mass analysis, peptide mapping and cysteine connectivity mapping) was performed by LC-MS/MS. CP-GMZ2'.10C resulted in similar purity, yield, structure and stability as compared to IP-GMZ2'.10C. CP-GMZ2'.10C and IP-GMZ2'.10C both elicited a high titer of transmission blocking (TB) antibodies in rodents. The intricate disulphide-bond connectivity of C-terminus Pfs48/45 was analysed by tandem mass spectrometry and was established for GMZ2'.10C and two reference fusion proteins encompassing similar parts of Pfs48/45. GMZ2'.10C, combining GMZ2' and correctly-folded Pfs48/45 can be produced by the Lactoccus lactis P170 based expression system in purity and quality for pharmaceutical development and elicit high level of TB antibodies. The cysteine connectivity for the 10C region of Pfs48/45 was revealed experimentally, providing an important guideline for employing the Pfs48/45 antigen in vaccine design.
Effect of malaria transmission reduction by insecticide-treated bed nets (ITNs) on the genetic diversity of Plasmodium falciparum merozoite surface protein (MSP-1) and circumsporozoite (CSP) in western Kenya.
Kariuki, Simon K; Njunge, James; Muia, Ann; Muluvi, Geofrey; Gatei, Wangeci; Ter Kuile, Feiko; Terlouw, Dianne J; Hawley, William A; Phillips-Howard, Penelope A; Nahlen, Bernard L; Lindblade, Kim A; Hamel, Mary J; Slutsker, Laurence; Shi, Ya Ping
Although several studies have investigated the impact of reduced malaria transmission due to insecticide-treated bed nets (ITNs) on the patterns of morbidity and mortality, there is limited information on their effect on parasite diversity. Sequencing was used to investigate the effect of ITNs on polymorphisms in two genes encoding leading Plasmodium falciparum vaccine candidate antigens, the 19 kilodalton blood stage merozoite surface protein-1 (MSP-1(19kDa)) and the Th2R and Th3R T-cell epitopes of the pre-erythrocytic stage circumsporozoite protein (CSP) in a large community-based ITN trial site in western Kenya. The number and frequency of haplotypes as well as nucleotide and haplotype diversity were compared among parasites obtained from children diversity of > 0.7. No MSP-1(19kDa) 3D7 sequence-types were detected in 1996 and the frequency was less than 4% in 2001. The CSP Th2R and Th3R domains were highly polymorphic with a total of 26 and 14 haplotypes, respectively detected in 1996 and 34 and 13 haplotypes in 2001, with an overall haplotype diversity of > 0.9 and 0.75 respectively. The frequency of the most predominant Th2R and Th3R haplotypes was 14 and 36%, respectively. The frequency of Th2R and Th3R haplotypes corresponding to the 3D7 parasite strain was less than 4% at both time points. There was no significant difference in nucleotide and haplotype diversity in parasite isolates collected at both time points. High diversity in these two genes has been maintained overtime despite marked reductions in malaria transmission due to ITNs use. The frequency of 3D7 sequence-types was very low in this area. These findings provide information that could be useful in the design of future malaria vaccines for deployment in endemic areas with high ITN coverage and in interpretation of efficacy data for malaria vaccines based on 3D7 parasite strains.
Full Text Available BACKGROUND: Congenital malaria, in which infants are directly infected with malaria parasites from their mother prior to or during birth, is a potentially life-threatening condition that occurs at relatively low rates in malaria-endemic regions. It is recognized as a serious problem in Plasmodium falciparum-endemic sub-Saharan Africa, where recent data suggests that it is more common than previously believed. In such regions where malaria transmission is high, neonates may be protected from disease caused by congenital malaria through the transfer of maternal antibodies against the parasite. However, in low P. vivax-endemic regions, immunity to vivax malaria is low; thus, there is the likelihood that congenital vivax malaria poses a more significant threat to newborn health. Malaria had previously been a major parasitic disease in China, and congenital malaria case reports in Chinese offer valuable information for understanding the risks posed by congenital malaria to neonatal health. As most of the literature documenting congenital malaria cases in China are written in Chinese and therefore are not easily accessible to the global malaria research community, we have undertaken an extensive review of the Chinese literature on this subject. METHODS/PRINCIPAL FINDINGS: Here, we reviewed congenital malaria cases from three major searchable Chinese journal databases, concentrating on data from 1915 through 2011. Following extensive screening, a total of 104 cases of congenital malaria were identified. These cases were distributed mainly in the eastern, central, and southern regions of China, as well as in the low-lying region of southwest China. The dominant species was P. vivax (92.50%, reflecting the malaria parasite species distribution in China. The leading clinical presentation was fever, and other clinical presentations were anaemia, jaundice, paleness, diarrhoea, vomiting, and general weakness. With the exception of two cases, all patients
Hollingdale, Michael R; Sedegah, Martha; Limbach, Keith
Malaria remains a major threat to endemic populations and travelers, including military personnel to these areas. A malaria vaccine is feasible, as radiation attenuated sporozoites induce nearly 100% efficacy. Areas covered: This review covers current malaria clinical trials using adenoviruses and pre-clinical research. Heterologous prime-boost regimens, including replication-deficient human adenovirus 5 (HuAd5) carrying malaria antigens, are efficacious. However, efficacy appears to be adversely affected by pre-existing anti-HuAd5 antibodies. Current strategies focus on replacing HuAd5 with rarer human adenoviruses or adenoviruses isolated from non-human primates (NHPs). The chimpanzee adenovirus ChAd63 is undergoing evaluation in clinical trials including infants in malaria-endemic areas. Key antigens have been identified and are being used alone, in combination, or with protein subunit vaccines. Gorilla adenoviruses carrying malaria antigens are also currently being evaluated in preclinical models. These replacement adenovirus vectors will be successfully used to develop vaccines against malaria, as well as other infectious diseases. Expert commentary: Simplified prime-boost single shot regimens, dry-coated live vector vaccines or silicon microneedle arrays could be developed for malaria or other vaccines. Replacement vectors with similar or superior immunogenicity have rapidly advanced, and several are now in extensive Phase 2 and beyond in malaria as well as other diseases, notably Ebola.
Malaria is a serious mosquito-borne disease that can lead to death. This podcast discusses malaria risk when traveling to tropical areas, as well as how to protect yourself and your family from malaria infection. Created: 5/15/2008 by National Center for Zoonotic, Vector-Borne, and Enteric Diseases (NCZVED). Date Released: 5/29/2008.
Turque, Oliver; Tsao, Tiffany; Li, Thomas; Zhang, Min
Malaria is a mosquito-borne infectious disease of humans and other animals. It is caused by the parasitic protozoan, Plasmodium. Sporozoites, the infectious form of malaria parasites, are quiescent when they remain in the salivary glands of the Anopheles mosquito until transmission into a mammalian host. Metamorphosis of the dormant sporozoite to its active form in the liver stage requires transcriptional and translational regulations. Here, we summarize recent advances in the translational repression of gene expression in the malaria sporozoite. In sporozoites, many mRNAs that are required for liver stage development are translationally repressed. Phosphorylation of eukaryotic Initiation Factor 2α (eIF2α) leads to a global translational repression in sporozoites. The eIF2α kinase, known as Upregulated in Infectious Sporozoite 1 (UIS1), is dominant in the sporozoite. The eIF2α phosphatase, UIS2, is translationally repressed by the Pumilio protein Puf2. This translational repression is alleviated when sporozoites are delivered into the mammalian host. PMID:28357358
Full Text Available Malaria is a mosquito-borne infectious disease of humans and other animals. It is caused by the parasitic protozoan, Plasmodium. Sporozoites, the infectious form of malaria parasites, are quiescent when they remain in the salivary glands of the Anopheles mosquito until transmission into a mammalian host. Metamorphosis of the dormant sporozoite to its active form in the liver stage requires transcriptional and translational regulations. Here, we summarize recent advances in the translational repression of gene expression in the malaria sporozoite. In sporozoites, many mRNAs that are required for liver stage development are translationally repressed. Phosphorylation of eukaryotic Initiation Factor 2α (eIF2α leads to a global translational repression in sporozoites. The eIF2α kinase, known as Upregulated in Infectious Sporozoite 1 (UIS1, is dominant in the sporozoite. The eIF2α phosphatase, UIS2, is translationally repressed by the Pumilio protein Puf2. This translational repression is alleviated when sporozoites are delivered into the mammalian host.
A linkage between presence of Sickle Haemoglobin (HbS) and protection from malaria infection and clinical manifestations in certain areas was suspected from early observations and progressively elucidated by more recent studies. Research has confirmed the abovementioned connection, but also clarified how such protection may be abolished by coexistence of sickle cell trait (HbS trait) and alpha thalassemia, which may explain the relatively low incidence of HbS trait in the Mediterranean. The mechanisms of such protective effect are now being investigated: factors of genetic, molecular and immunological nature are prominent. As for genetic factors attention is given to the role of the red blood cell (RBC) membrane complement regulatory proteins as polymorphisms of these components seem to be associated with resistance to severe malaria; genetic ligands like the Duffy group blood antigen, necessary for erythrocytic invasion, and human protein CD36, a major receptor for P. falciparum-infected RBC's, are also under scrutiny: attention is focused also on plasmodium erythrocyte-binding antigens, which bind to RBC surface components. Genome-wide linkage and association studies are now carried out too, in order to identify genes associated with malaria resistance. Only a minor role is attributed to intravascular sickling, phagocytosis and haemolysis, while specific molecular mechanisms are the object of intensive research: among these a decisive role is played by a biochemical sequence, involving activation of haeme oxygenase (HMO-1), whose effect appears mediated by carbon monoxide (CO). A central role in protection from malaria is also played by immunological factors, which may stimulate antibody production to plasmodium antigens in the early years of life; the role of agents like pathogenic CD8 T-cells has been suggested while the effects of molecular actions on the immunity mechanism are presently investigated. It thus appears that protection from malaria can be
Full Text Available Abstract Background Malaria cases attributed to Plasmodium falciparum account for approximately 600,000 deaths yearly, mainly in African children. The gold standard method to diagnose malaria requires the visualization of the parasite in blood. The role of non-invasive diagnostic methods to diagnose malaria remains unclear. Methods A protocol was optimized to deplete highly abundant proteins from saliva to improve the dynamic range of the proteins identified and assess their suitability as candidate biomarkers of malaria infection. A starch-based amylase depletion strategy was used in combination with four different lectins to deplete glycoproteins (Concanavalin A and Aleuria aurantia for N-linked glycoproteins; jacalin and peanut agglutinin for O-linked glycoproteins. A proteomic analysis of depleted saliva samples was performed in 17 children with fever and a positive–malaria slide and compared with that of 17 malaria-negative children with fever. Results The proteomic signature of malaria-positive patients revealed a strong up-regulation of erythrocyte-derived and inflammatory proteins. Three P. falciparum proteins, PFL0480w, PF08_0054 and PFI0875w, were identified in malaria patients and not in controls. Aleuria aurantia and jacalin showed the best results for parasite protein identification. Conclusions This study shows that saliva is a suitable clinical specimen for biomarker discovery. Parasite proteins and several potential biomarkers were identified in patients with malaria but not in patients with other causes of fever. The diagnostic performance of these markers should be addressed prospectively.
Full Text Available This paper is an overview of vaccine antigens against malaria produced in plants. Plant-based expression systems represent an interesting production platform due to their reduced manufacturing costs and high scalability. At present, different Plasmodium antigens and expression strategies have been optimized in plants. Furthermore, malaria antigens are one of the few examples of eukaryotic proteins with vaccine value expressed in plants, making plant-derived malaria antigens an interesting model to analyze. Up to now, malaria antigen expression in plants has allowed the complete synthesis of these vaccine antigens, which have been able to induce an active immune response in mice. Therefore, plant production platforms offer wonderful prospects for improving the access to malaria vaccines.
Cates, Jordan E.; Unger, Holger W.; Briand, Valerie
were identified by the Maternal Malaria and Malnutrition (M3) initiative using a convenience sampling approach and were eligible for pooling given adequate ethical approval and availability of essential variables. Study-specific adjusted effect estimates were calculated using inverse probability...... be multiplicative interaction between malaria infection at enrollment and low MUAC within studies conducted in Africa; however, this finding was not consistent on the additive scale, when accounting for multiple comparisons, or when using other definitions of malaria and malnutrition. The major limitations...... of the study included availability of only 2 cross-sectional measurements of malaria and the limited availability of ultrasound-based pregnancy dating to assess impacts on preterm birth and fetal growth in all studies. Conclusions : Pregnant women with malnutrition and malaria infection are at increased risk...
Kurth, Florian; Develoux, Michel; Mechain, Matthieu
BACKGROUND: Malaria remains one of the most serious infections for travellers to tropical countries. Due to the lack of harmonized guidelines a large variety of treatment regimens is used in Europe to treat severe malaria. METHODS: The European Network for Tropical Medicine and Travel Health (Trop......Net) conducted an 8-year, multicentre, observational study to analyse epidemiology, treatment practices and outcomes of severe malaria in its member sites across Europe. Physicians at participating TropNet centres were asked to report pseudonymized retrospective data from all patients treated at their centre...... for microscopically confirmed severe Plasmodium falciparum malaria according to the 2006 WHO criteria. RESULTS: From 2006 to 2014 a total of 185 patients with severe malaria treated in 12 European countries were included. Three patients died, resulting in a 28-day survival rate of 98.4%. The majority of infections...
Patrick Emmet Duffy
Full Text Available Malaria during pregnancy can be severe in non-immune women, but in areas of stable transmission, where women are semi-immune and often asymptomatic during infection, malaria is an insidious cause of disease and death for mothers and their offspring. Sequelae, such as severe anaemia and hypertension in the mother and low birth weight and infant mortality in the offspring, are often not recognised as consequences of infection. Pregnancy malaria, caused by Plasmodium falciparum, is mediated by infected erythrocytes (IEs that bind to chondroitin sulphate A and are sequestered in the placenta. These parasites have a unique adhesion phenotype and distinct antigenicity, which indicates that novel targets may be required for development of an effective vaccine. Women become resistant to malaria as they acquire antibodies against placental IE, which leads to higher haemoglobin levels and heavier babies. Proteins exported from the placental parasites have been identified, including both variant and conserved antigens, and some of these are in preclinical development for vaccines. A vaccine that prevents P. falciparum malaria in pregnant mothers is feasible and would potentially save hundreds of thousands of lives each year.
Alberto L. García-Basteiro
Full Text Available Eliciting an effective malaria vaccine has been the goal of the scientific community for many years. A malaria vaccine, added to existing tools and strategies, would further prevent and decrease the unacceptable malaria morbidity and mortality burden. Great progress has been made over the last decade, with some vaccine candidates in the clinical phases of development. The RTS,S malaria vaccine candidate, based on a recombinant P. falciparum protein, is the most advanced of such candidates, currently undergoing a large phase III trial. RTS,S has consistently shown an efficacy of around 50% against the first clinical episode of malaria, with protection in some cases extending up to 4 years of duration. Thus, it is hoped that this candidate vaccine will eventually become the first licensed malaria vaccine. This first vaccine against a human parasite is a groundbreaking achievement, but improved malaria vaccines conferring higher protection will be needed if the aspiration of malaria eradication is to be achieved
Spottiswoode, Natasha; Armitage, Andrew E; Williams, Andrew R; Fyfe, Alex J; Biswas, Sumi; Hodgson, Susanne H; Llewellyn, David; Choudhary, Prateek; Draper, Simon J; Duffy, Patrick E; Drakesmith, Hal
Epidemiological observations have linked increased host iron with malaria susceptibility, and perturbed iron handling has been hypothesized to contribute to the potentially life-threatening anemia that may accompany blood-stage malaria infection. To improve our understanding of these relationships, we examined the pathways involved in regulation of the master controller of iron metabolism, the hormone hepcidin, in malaria infection. We show that hepcidin upregulation in Plasmodium berghei murine malaria infection was accompanied by changes in expression of bone morphogenetic protein (BMP)/sons of mothers against decapentaplegic (SMAD) pathway target genes, a key pathway involved in hepcidin regulation. We therefore investigated known agonists of the BMP/SMAD pathway and found that Bmp gene expression was not increased in infection. In contrast, activin B, which can signal through the BMP/SMAD pathway and has been associated with increased hepcidin during inflammation, was upregulated in the livers of Plasmodium berghei -infected mice; hepatic activin B was also upregulated at peak parasitemia during infection with Plasmodium chabaudi Concentrations of the closely related protein activin A increased in parallel with hepcidin in serum from malaria-naive volunteers infected in controlled human malaria infection (CHMI) clinical trials. However, antibody-mediated neutralization of activin activity during murine malaria infection did not affect hepcidin expression, suggesting that these proteins do not stimulate hepcidin upregulation directly. In conclusion, we present evidence that the BMP/SMAD signaling pathway is perturbed in malaria infection but that activins, although raised in malaria infection, may not have a critical role in hepcidin upregulation in this setting. Copyright © 2017 Spottiswoode et al.
Petersen, E; Høgh, B; Dziegiel, M
The IgG and IgM antibody responses to the C-terminal 783 amino acids of the P. falciparum glutamate-rich protein, GLURP489-1271, expressed as an E. coli fusion protein, the IgG response to a 18-mer synthetic peptide EDKNEKGQHEIVEVEEIL (GLURP899-916) representing the C-terminal repeats of GLURP......, and a synthetic peptide (EENV)6 representing the C-terminal repeats from Pf155/RESA, were investigated longitudinally in 13 children and 7 adults living under conditions of continuous, intense malaria transmission. Some subjects did not recognize the antigens after malaria infection, and in subjects recognizing...... the antigens, the responses were often short-lived. In adults, the antibody responses to the GLURP489-1271 fusion protein and the (EENV)6 peptide peaked after 2 weeks, and not all individuals responded to all antigens. The antibody response, even against large fragments of conserved antigens, is not uniformly...
... Facebook Tweet Share Compartir The Disease What is Malaria? Malaria is a serious and sometimes fatal disease ... cycle of disease and poverty. How People Get Malaria (Transmission) How is malaria transmitted? Usually, people get ...
Full Text Available Abstract Background Reversible protein phosphorylation is relatively unexplored in the intracellular protozoa of the Apicomplexa family that includes the genus Plasmodium, to which belong the causative agents of malaria. Members of the PP1 family represent the most highly conserved protein phosphatase sequences in phylogeny and play essential regulatory roles in various cellular pathways. Previous evidence suggested a PP1-like activity in Plasmodium falciparum, not yet identified at the molecular level. Results We have identified a PP1 catalytic subunit from P. falciparum and named it PfPP1. The predicted primary structure of the 304-amino acid long protein was highly similar to PP1 sequences of other species, and showed conservation of all the signature motifs. The purified recombinant protein exhibited potent phosphatase activity in vitro. Its sensitivity to specific phosphatase inhibitors was characteristic of the PP1 class. The authenticity of the PfPP1 cDNA was further confirmed by mutational analysis of strategic amino acid residues important in catalysis. The protein was expressed in all erythrocytic stages of the parasite. Abrogation of PP1 expression by synthetic short interfering RNA (siRNA led to inhibition of parasite DNA synthesis. Conclusions The high sequence similarity of PfPP1 with other PP1 members suggests conservation of function. Phenotypic gene knockdown studies using siRNA confirmed its essential role in the parasite. Detailed studies of PfPP1 and its regulation may unravel the role of reversible protein phosphorylation in the signalling pathways of the parasite, including glucose metabolism and parasitic cell division. The use of siRNA could be an important tool in the functional analysis of Apicomplexan genes.
Alencar, Aristóteles Comte Filho de, E-mail: firstname.lastname@example.org [Universidade Federal do Amazonas, Manaus, AM (Brazil); Lacerda, Marcus Vinícius Guimarães de [Fundação de Medicina Tropical Dr. Heitor Vieira Dourado (FMT-HVD), Manaus, AM (Brazil); Okoshi, Katashi; Okoshi, Marina Politi [Faculdade de Medicina de Botucatu (Unesp), Botucatu, SP (Brazil)
Involvement of the cardiovascular system in patients with infectious and parasitic diseases can result from both intrinsic mechanisms of the disease and drug intervention. Malaria is an example, considering that the endothelial injury by Plasmodium-infected erythrocytes can cause circulatory disorders. This is a literature review aimed at discussing the relationship between malaria and endothelial impairment, especially its effects on the cardiovascular system. We discuss the implications of endothelial aggression and the interdisciplinarity that should guide the malaria patient care, whose acute infection can contribute to precipitate or aggravate a preexisting heart disease.
Alencar, Aristóteles Comte Filho de; Lacerda, Marcus Vinícius Guimarães de; Okoshi, Katashi; Okoshi, Marina Politi
Involvement of the cardiovascular system in patients with infectious and parasitic diseases can result from both intrinsic mechanisms of the disease and drug intervention. Malaria is an example, considering that the endothelial injury by Plasmodium-infected erythrocytes can cause circulatory disorders. This is a literature review aimed at discussing the relationship between malaria and endothelial impairment, especially its effects on the cardiovascular system. We discuss the implications of endothelial aggression and the interdisciplinarity that should guide the malaria patient care, whose acute infection can contribute to precipitate or aggravate a preexisting heart disease
Mosnier, Laurent O; Lavstsen, Thomas
and therapeutic options, for which understanding of the mechanisms that cause death and disability in malaria is essential. The recent discoveries that certain variants of P. falciparum erythrocyte membrane protein 1 (PfEMP1) expressed on infected erythrocytes are intimately linked to the precipitation of severe...... the new paradigm that EPCR plays a central role in the pathogenesis of severe malaria. Thus, targeting of the PfEMP1-EPCR interaction and restoring the functionality of the PC system may provide new strategies for the development of novel adjuvant therapies for severe malaria....
Malaria in the 21st Century” was held at ... seconds, and more than one million deaths occur annually from this disease. ... Biological control, for example the use of predatory fish against mosquito larvae and the use of other predatory insects.
Hughes, David Peter; Boomsma, Jacobus Jan
)  highlighted the back-to-back articles in Science 3 and 4 that demonstrated the potential biocontrol of malaria by targeting mosquitoes with entomopathogenic fungi (Metarhizium and Beauveria spp.). The wide impact of the original articles and the need to find alternatives to pesticidal control...... where malaria is endemic, humanity cannot afford shortcuts, because any failures owing to poor management or premature implementation will reduce local governmental support rather than enhance it (Andrew Read, pers. commun.). Therefore, if we are to ‘muscle out malaria', well...... of key importance, and the new focus on fungal biocontrol of malaria should therefore act as a catalyst for further research on the basic biology of fungal pathogens. Understanding morphological, biochemical or immune system-based resistance to insect pathogenic fungi will be easier if we know...
1 million people die in the world from malaria annually, 800,000 of whom are 5 year old children in Sub-Sahara Africa. Further it affects 270 million people. In fact, 110 million develop malaria, 90 million of whom are from Sub-Saharan Africa. Thus WHO has introduced a new world initiative for malaria control to reverse the worsening trend that began in the mid 1970s. In October 1991, 150 officials from 50 African, Asian, and Latin American countries and participants from UN cooperation and development agencies and bilateral agencies attended an interregional conference at the WHO Regional office for Africa in Brazzaville, Congo. It strove to evaluate malaria situations specific to Africa, to update the malaria control plan in Africa, and to contribute to the development of an implementable world strategy. This world strategy needs to consider the local situation and encourage participation of the government and people of affected countries. Further individuals, communities, and various sectors of the national economy including those involved in health, education, development, and agriculture need to participate in malaria control. In addition, for this strategy to work, most countries must strengthen the management and financing of health services to meet their needs. For example, local populations must share local operating costs such as those for essential drugs and mosquito control operations. Community participation must also include personal protection such as impregnated bed nets and environmental measures. Besides malaria control must be integrated into the existing health system at country, provincial, and peripheral levels. In sum, improved case management, control of malaria transmission, and prevention and control of epidemics form the basis for the new strategy.
Jesus R. Alvarez
Full Text Available Recently, there has been a resurgence of malaria in densely populated areas of the United States secondary to human migration from endemic areas where factors such as cessation of vector control, vector resistance to insecticides, disease resistance to drugs, environmental changes, political instability, and indifference, have played a role for malaria becoming an overwhelming infection of these tropical underdeveloped countries. It is important for health care providers of gravida to be alert of the disease and its effects on pregnancy.
Even now, malaria treatment should only be administered after laboratory confirmation. There are several principal methods for diagnosing malaria. All these methods have their disadvantages.Presumptive treatment of malaria is widely practiced where laboratory tests are not readily available. Microscopy of Giemsa-stained thick and thin blood films remains the gold standard for the diagnosis of malaria infection. The technique of slide preparation, staining and reading are well known and standardized, and so is the estimate of the parasite density and parasite stages. Microscopy is not always available or feasible at primary health services in limited resource settings due to cost, lack of skilled manpower, accessories and reagents required. Rapid diagnostic tests (RDTs) are potential tools for parasite-based diagnosis since the tests are accurate in detecting malaria infections and are easy to use. The test is based on the capture of parasite antigen that released from parasitized red blood cells using monoclonal antibodies prepared against malaria antigen target. Polymerase Chain Reaction (PCR), depend on DNA amplification approaches and have higher sensitivity than microscopy. PCR it is not widely used due to the lack of a standardized methodology, high costs, and the need for highly-trained staff.
Full Text Available Abstract Malaria is still the global health problems, World Health Organization estimates that malaria causes death of approximately 660.000 in 2010, most of the age of the children in the region of sub-Saharan Africa. World Malaria Day 2013 assigned the theme “Invest in the future. Defeat malaria”. It takes political will and collective action to jointly combat malaria through malaria elimination. Needed more new donors to be involved in global partnerships against malaria. These partnerships exist, one of which is support of funding or facility for malaria endemic countries which do not have sufficient resources to control malaria. A lot of effort has been done or is still in the development stage. The use of long-lasting insecticidal nets appropriately can reduce malaria cases. The use of rapid diagnostic test, especially in remote areas and health facility with no microscopy, is very beneficial for patients to get prompt treatment. The control of malaria through integrated vector management is a rational decision making process to optimize the use of resources in the control of vector. Sterile insect technique has a promising prospect and expected to replace the role of chemical insecticides that have negative impact both on the environment and target vector (resistance. Keywords: Malaria, long-lasting insecticidal nets, rapid diagnostic test Abstrak Malaria masih menjadi masalah kesehatan dunia, Organisasi Kesehatan Dunia (WHO memperkirakan malaria menyebabkan kurang lebih 660.000 kematian pada tahun 2010, kebanyakan usia anak-anak di wilayah Sub-Sahara Afrika. Pada peringatan hari malaria dunia tahun 2013 ditetapkan tema “Investasi di masa depan. Taklukkan malaria”. Dibutuhkan kemauan politik dan tindakan kolektif untuk bersama-sama memerangi malaria melalui gerakan eliminasi malaria. Diperlukan lebih banyak donor baru untuk turut terlibat dalam kemitraan global melawan malaria. Wujud kemitraan tersebut salah satunya adalah
Joachim Michael Matz
Full Text Available Summary: Proteins of the stomatin/prohibitin/flotillin/HfIK/C (SPFH family are membrane-anchored and perform diverse cellular functions in different organelles. Here, we investigate the SPFH proteins of the murine malaria model parasite Plasmodium berghei, the conserved prohibitin 1, prohibitin 2, and stomatin-like protein and an unusual prohibitin-like protein (PHBL. The SPFH proteins localize to the parasite mitochondrion. While the conserved family members could not be deleted from the Plasmodium genome, PHBL was successfully ablated, resulting in impaired parasite fitness and attenuated virulence in the mammalian host. Strikingly, PHBL-deficient parasites fail to colonize the Anopheles vector because of complete arrest during ookinete development in vivo. We show that this arrest correlates with depolarization of the mitochondrial membrane potential (ΔΨmt. Our results underline the importance of SPFH proteins in the regulation of core mitochondrial functions and suggest that fine-tuning of ΔΨmt in malarial parasites is critical for colonization of the definitive host. : Matz et al. present an experimental genetics study of an unusual prohibitin-like protein in the malaria parasite and find that it regulates mitochondrial membrane polarity. Ablation of this protein causes almost complete mitochondrial depolarization in the mosquito vector, which, in turn, leads to a block in malaria parasite transmission. Keywords: Plasmodium berghei, malaria, SPFH, prohibitin, stomatin-like protein, mitochondrion, membrane potential, ookinete, transmission
Full Text Available Many critical events in the Plasmodium life cycle rely on the controlled release of Ca²⁺ from intracellular stores to activate stage-specific Ca²⁺-dependent protein kinases. Using the motility of Plasmodium berghei ookinetes as a signalling paradigm, we show that the cyclic guanosine monophosphate (cGMP-dependent protein kinase, PKG, maintains the elevated level of cytosolic Ca²⁺ required for gliding motility. We find that the same PKG-dependent pathway operates upstream of the Ca²⁺ signals that mediate activation of P. berghei gametocytes in the mosquito and egress of Plasmodium falciparum merozoites from infected human erythrocytes. Perturbations of PKG signalling in gliding ookinetes have a marked impact on the phosphoproteome, with a significant enrichment of in vivo regulated sites in multiple pathways including vesicular trafficking and phosphoinositide metabolism. A global analysis of cellular phospholipids demonstrates that in gliding ookinetes PKG controls phosphoinositide biosynthesis, possibly through the subcellular localisation or activity of lipid kinases. Similarly, phosphoinositide metabolism links PKG to egress of P. falciparum merozoites, where inhibition of PKG blocks hydrolysis of phosphatidylinostitol (4,5-bisphosphate. In the face of an increasing complexity of signalling through multiple Ca²⁺ effectors, PKG emerges as a unifying factor to control multiple cellular Ca²⁺ signals essential for malaria parasite development and transmission.
Background: Malaria is a preventable and treatable disease associated with high morbidity and mortality. It is the 3rd leading cause of death for children under five years worldwide. Home-based management of malaria may go a long way in reducing the attending morbidity and mortality associated with malaria in this group ...
Discriminating malaria from dengue fever in endemic areas: clinical and biological criteria, prognostic score and utility of the C-reactive protein: a retrospective matched-pair study in French Guiana.
Full Text Available BACKGROUND: Dengue and malaria are two major public health concerns in tropical settings. Although the pathogeneses of these two arthropod-borne diseases differ, their clinical and biological presentations are unspecific. During dengue epidemics, several hundred patients with fever and diffuse pain are weekly admitted at the emergency room. It is difficult to discriminate them from patients presenting malaria attacks. Furthermore, it may be impossible to provide a parasitological microscopic examination for all patients. This study aimed to establish a diagnostic algorithm for communities where dengue fever and malaria occur at some frequency in adults. METHODOLOGY/PRINCIPAL FINDINGS: A sub-study using the control groups of a case-control study in French Guiana--originally designed to compare dengue and malaria co-infected cases to single infected cases--was performed between 2004 and 2010. In brief, 208 patients with malaria matched to 208 patients with dengue fever were compared in the present study. A predictive score of malaria versus dengue was established using .632 bootstrap procedures. Multivariate analysis showed that male gender, age, tachycardia, anemia, thrombocytopenia, and CRP>5 mg/l were independently associated with malaria. The predictive score using those variables had an AUC of 0.86 (95%CI: 0.82-0.89, and the CRP was the preponderant predictive factor. The sensitivity and specificity of CRP>5 mg/L to discriminate malaria from dengue were of 0.995 (95%CI: 0.991-1 and 0.35 (95%CI 0.32-0.39, respectively. CONCLUSIONS/SIGNIFICANCE: The clinical and biological score performed relatively well for discriminating cases of dengue versus malaria. Moreover, using only the CRP level turned to be a useful biomarker to discriminate feverish patients at low risk of malaria in an area where both infections exist. It would avoid more than 33% of unnecessary parasitological examinations with a very low risk of missing a malaria attack.
triggering control programme action, and detecting gametocyte carriers, who may ... clinical malaria does not generally apply to local-born populations, although it ... deficiencies in the quality of malaria diagnosis in routine laboratories. Quality ...
Malaria currently remains the highest killer disease nationwide despite existing control measures. Malaria vaccine ... that malaria could be eliminated or at least controlled. However, because of changes in vector behaviour, drug resistance, manpower constraints for public ..... Although animal host models are different from ...
die every day from malaria, conventional efforts to control the disease have not worked. Malaria parasites are .... and other animals. Mosquito nets. Provide insecticide-treated bednets to groups at high risk for malaria, namely young children and pregnant women, through partnerships with nongovernmental organizations ...
Zimmerman Peter A
Full Text Available Abstract Background Toll-like receptors (TLR and related downstream signaling pathways of innate immunity have been implicated in the pathogenesis of Plasmodium falciparum malaria. Because of their potential role in malaria pathogenesis, polymorphisms in these genes may be under selective pressure in populations where this infectious disease is endemic. Methods A post-PCR Ligation Detection Reaction-Fluorescent Microsphere Assay (LDR-FMA was developed to determine the frequencies of TLR2, TLR4, TLR9, MyD88-Adaptor Like Protein (MAL single nucleotide polymorphisms (SNPs, and TLR2 length polymorphisms in 170 residents of two regions of Kenya where malaria transmission is stable and high (holoendemic or episodic and low, 346 residents of a malaria holoendemic region of Papua New Guinea, and 261 residents of North America of self-identified ethnicity. Results The difference in historical malaria exposure between the two Kenyan sites has significantly increased the frequency of malaria protective alleles glucose-6-phoshpate dehydrogenase (G6PD and Hemoglobin S (HbS in the holoendemic site compared to the episodic transmission site. However, this study detected no such difference in the TLR2, TLR4, TLR9, and MAL allele frequencies between the two study sites. All polymorphisms were in Hardy Weinberg Equilibrium in the Kenyan and Papua New Guinean populations. TLR9 SNPs and length polymorphisms within the TLR2 5' untranslated region were the only mutant alleles present at a frequency greater than 10% in all populations. Conclusion Similar frequencies of TLR2, TLR4, TLR9, and MAL genetic polymorphisms in populations with different histories of malaria exposure suggest that these innate immune pathways have not been under strong selective pressure by malaria. Genotype frequencies are consistent with Hardy-Weinberg Equilibrium and the Neutral Theory, suggesting that genetic drift has influenced allele frequencies to a greater extent than selective
Spence, Philip J; Cunningham, Deirdre; Jarra, William; Lawton, Jennifer; Langhorne, Jean; Thompson, Joanne
The rodent malaria parasite Plasmodium chabaudi chabaudi shares many features with human malaria species, including P. falciparum, and is the in vivo model of choice for many aspects of malaria research in the mammalian host, from sequestration of parasitized erythrocytes, to antigenic variation and host immunity and immunopathology. This protocol describes an optimized method for the transformation of mature blood-stage P.c. chabaudi and a description of a vector that targets efficient, single crossover integration into the P.c. chabaudi genome. Transformed lines are reproducibly generated and selected within 14-20 d, and show stable long-term protein expression even in the absence of drug selection. This protocol, therefore, provides the scientific community with a robust and reproducible method to generate transformed P.c. chabaudi parasites expressing fluorescent, bioluminescent and model antigens that can be used in vivo to dissect many of the fundamental principles of malaria infection.
Kempaiah, Prakasha; Dokladny, Karol; Karim, Zachary
by decreased HSPA1A, a heat shock protein (Hsp) 70 coding gene. Hsp70 is a ubiquitous chaperone that regulates Nuclear Factor-kappa B (NF-κB) signaling and production of pro-inflammatory cytokines known to be important in malaria pathogenesis (e.g., IL-1β, IL-6 and TNF-α). Since the role of host Hsp70...... in malaria pathogenesis is unexplored, we investigated Hsp70 and molecular pathways in children with SMA. Validation experiments revealed that leukocytic HSP70 transcripts were reduced in SMA relative to non-severe malaria, and that intraleukocytic hemozoin (PfHz) was associated with lower HSP70. HSP70...... was correlated with reticulocyte production and Hb. Since glutamine (Gln) up-regulates Hsp70, modulates NF-κB activation, and attenuates over-expression of pro-inflammatory cytokines, circulating Gln was measured in children with malaria. Reduced Gln was associated with increased risk of developing SMA...
B S GARG
Full Text Available The last few years have seen a marked change in the understanding of malaria mmunology.We have very little knowledge on immunity of Malaria based on experiments in humanbeings due to ethical reasons. Whatsoever our knowledge exists at present is based onexperimentas in mice and monkey. However it is clear that it is sporzoite or merozoitewhich is directly exposed to our immune system in the life cycle of Malaria parasite. On thebasis of human experiments we can draw inference that immunity to malaria is species.specific (on cross immunity, stage specific and strain specific as well acquired in the response to surface antigen and relapsed antigen although the parasite also demonstrates escape machanism to immune system.So the host system kills or elimi nate the parasite by means of (a Antbody to extracell~ular form of parasite with the help of mechanism of Block invasion, Agglutination or opsonization and/or (b Cellular machanism-either by phago-cytosis of parasite or by antibody dependent cellular cytotoxicity ABCC (? or by effects of mediators like tumor necrosis fJ.ctor (TNF in cerebaral malaria or crisis forming factor as found in sudan or by possible role of lysis mechanism.However, inspite of all these theories the parasite has been able to invade the immunesystem by virtue of its intracellular development stage specificity, sequestration in capillaries and also by its unusual characteristics of antigenic diversity and antigenic variation.
This article presents the activities under WHO's Roll Back Malaria (RBM) program in Asia, particularly in Nepal, Indonesia, India, Bangladesh, Sri Lanka and the Philippines. In India, the RBM program will start in 5 districts with a major malaria problem. A national committee has been formed by researchers, which will be able to provide operational and strategic support and research expertise in relation to malaria. In Bangladesh, the RBM program was initiated in the sparsely populated hill tract areas of Banderban and Chittagong where access to health care is very poor. At the district level, effective partnerships with private practitioners, politicians, community leaders, school teachers, the press and district Ministry of Health officials are operating to plan for rolling back malaria. In Myanmar, Cambodia, Lao People's Democratic Republic, Yunnan province of China, Vietnam, and Thailand, the focus of the RBM program was to move health care closer to the malaria-infected communities. WHO¿s Global Health Leadership Fellowship Programme, supported by the UN Foundation and Rockefeller Foundation, enables potential leaders to experience the work of UN agencies and contribute to the work of the organization for 2 years. Three out of four persons appointed to the RBM program received prestigious awards: Dr. Paola Marchesini of Brazil; Dr. Tieman Diarra of Mali; and Dr. Bob Taylor of the UK.
Boudová, Sarah; Walldorf, Jenny A; Bailey, Jason A; Divala, Titus; Mungwira, Randy; Mawindo, Patricia; Pablo, Jozelyn; Jasinskas, Algis; Nakajima, Rie; Ouattara, Amed; Adams, Matthew; Felgner, Philip L; Plowe, Christopher V; Travassos, Mark A; Laufer, Miriam K
Maternal antibodies may play a role in protecting newborns against malaria disease. Plasmodium falciparum parasite surface antigens are diverse, and protection from infection requires allele-specific immunity. Although malaria-specific antibodies have been shown to cross the placenta, the extent to which antibodies that respond to the full repertoire of diverse antigens are transferred from the mother to the infant has not been explored. Understanding the breadth of maternal antibody responses and to what extent these antibodies are transferred to the child can inform vaccine design and evaluation. We probed plasma from cord blood and serum from mothers at delivery using a customized protein microarray that included variants of malaria vaccine target antigens to assess the intensity and breadth of seroreactivity to three malaria vaccine candidate antigens in mother-newborn pairs in Malawi. Among the 33 paired specimens that were assessed, mothers and newborns had similar intensity and repertoire of seroreactivity. Maternal antibody levels against vaccine candidate antigens were the strongest predictors of infant antibody levels. Placental malaria did not significantly impair transplacental antibody transfer. However, mothers with placental malaria had significantly higher antibody levels against these blood-stage antigens than mothers without placental malaria. The repertoire and levels of infant antibodies against a wide range of malaria vaccine candidate antigen variants closely mirror maternal levels in breadth and magnitude regardless of evidence of placental malaria. Vaccinating mothers with an effective malaria vaccine during pregnancy may induce high and potentially protective antibody repertoires in newborns. Copyright © 2017 American Society for Microbiology.
Gallup, J L; Sachs, J D
Malaria and poverty are intimately connected. Controlling for factors such as tropical location, colonial history, and geographical isolation, countries with intensive malaria had income levels in 1995 of only 33% that of countries without malaria, whether or not the countries were in Africa. The high levels of malaria in poor countries are not mainly a consequence of poverty. Malaria is geographically specific. The ecological conditions that support the more efficient malaria mosquito vectors primarily determine the distribution and intensity of the disease. Intensive efforts to eliminate malaria in the most severely affected tropical countries have been largely ineffective. Countries that have eliminated malaria in the past half century have all been either subtropical or islands. These countries' economic growth in the 5 years after eliminating malaria has usually been substantially higher than growth in the neighboring countries. Cross-country regressions for the 1965-1990 period confirm the relationship between malaria and economic growth. Taking into account initial poverty, economic policy, tropical location, and life expectancy, among other factors, countries with intensive malaria grew 1.3% less per person per year, and a 10% reduction in malaria was associated with 0.3% higher growth. Controlling for many other tropical diseases does not change the correlation of malaria with economic growth, and these diseases are not themselves significantly negatively correlated with economic growth. A second independent measure of malaria has a slightly higher correlation with economic growth in the 1980-1996 period. We speculate about the mechanisms that could cause malaria to have such a large impact on the economy, such as foreign investment and economic networks within the country.
Full Text Available The proportion of imported malaria cases due to immigrants in Europe has increased during the lasts decades, being the higher rates for those settled immigrants who travel to visit friends and relatives (VFRs at their country of origin. Cases are mainly due to P. falciparum and Sub-Saharan Africa is the most common origin. Clinically, malaria in immigrants is characterized by a mild clinical presentation with even asymptomatic o delayed malaria cases and low parasitemic level. These characteristics may be explained by a semi-immunity acquired after long periods of time exposed to stable transmission of malaria. Malaria cases among immigrants, even those asymptomatic patients with sub-microscopic parasitemia, could increase the risk of transmission and reintroduction of malaria in certain areas with the adequate vectors and climate conditions. Moreover imported malaria cases by immigrants can also play an important role in the non-vectorial transmission out of endemic area, by blood transfusions, organ transplantation or congenital or occupational exposures. Probably, out of endemic areas, screening of malaria among recent arrived immigrants coming from malaria endemic countries should be performed. These aim to reduce the risk of clinical malaria in the individual as well as to prevent autochthonous transmission of malaria in areas where it had been eradicated.
Patarroyo, Manuel Elkin
La malaria es una enfermedad parasitaria producida por la picadura de un mosquito; una afección que en el año 2015 registró 212 millones de casos y 429.000 muertes. Cada dos minutos, la malaria provocó la muerte de un niño menor de cinco años en todo el mundo. Diferentes científicos a lo largo de todo el mundo han hecho múltiples intentos para combatir esta enfermedad con una vacuna efectiva que pueda erradicarla de raíz.
Age and puberty have been found to contribute to malaria resistance. It is expected that knowledge of natural resistance to malaria may aid in developing Vaccines against this deadly disease. Keywords: malaria resistance, puberty, malaria economy, malaria vaccine. Nigerian Medical Practitioner Vol. 49(5) 2006: 133-142 ...
Jakobsen, P H; Theander, T G; Hviid, L
Synthetic P. falciparum peptides were evaluated as tools in epidemiological investigations of malaria. Plasma IgM and IgG antibody reactivities against synthetic peptides covering sequences of glutamate-rich protein (GLURP) and acidic-basic repeat antigen (ABRA) were measured by ELISA...... in individuals from malaria-endemic areas of Sudan, Indonesia and The Gambia to study antibody responses to these peptides in donors living in areas of different malaria endemicity. IgG and IgM reactivities to the peptides increased with malaria endemicity, although there were no differences in reactivities...... tested were shortlived in most patients. In Gambian children with malaria, IgM reactivities but not IgG antibody reactivities against the ABRA peptide were higher in those with mild malaria than in those with severe malaria. The peptides may be useful in future epidemiological studies, especially...
Rauber, K.; Enkerlin, H.L.; Riemann, H.; Schoeppe, W.; Frankfurt Univ.
We report on the two different types of pulmonary manifestations in acute plasmodium falciparum malaria. The more severe variant shows long standing interstitial pulmonary infiltrates, whereas in the more benign courses only short-term pulmonary edemas are visible. (orig.) [de
malaria in Vietnam was resisent to drugs such as chloroquine , generally recognized since World War ii as satisfactory antimalarial agents. The urgent...known to have antimalarial activity; (3) structural analogues of compounds found active in our test system and representing several novel chemical
Durrheim, Karen Barnes. Objectives. To assess the therapeutic efficacy of sulfadoxine- pyrimethamine (SP) after 5 years of use as first-line treatment of uncomplicated Plasmodium falciparum malaria, and thus guide the selection of artemisinin-based combination therapy in Mpumalanga, South Africa. Design. An open-label ...
The mineral rich territory of the Yanomami Indians of northern Brazil has been invaded by miners--who have destroyed the environment and introduced disease. Médecins Sans Frontières agreed to help combat the malaria epidemic. Conditions in the rainforest and villages and the health care facilities are described. Mere medical aid cannot prevent the Yanomami from being decimated.
to allow prompt and accurate treatment of malaria in areas out .... It is essential to seek medical advice promptly if ... Not ideal for machine operators, drivers or those that work at heights .... with food that contains oil e.g. chips, bread and butter.
major strategies for reducing the burden of malaria, therefore ... children. The incidence of history of fever, indicative of malaria in children of the respondents within one ... interventions for the control of childhood malaria. ..... Yellow eyes. 20.
... Malaria About Malaria FAQs Fast Facts Disease Biology Ecology Human Factors Sickle Cell Mosquitoes Parasites Where Malaria ... medicines, also consider the possibility of drug-drug interactions with other medicines that the person might be ...
Pratt-Riccio, Lilian Rose; Bianco, Cesare; Totino, Paulo Renato Rivas
The glutamate-rich protein (GLURP) is an exoantigen expressed in all stages of the Plasmodium falciparum life cycle in humans. Anti-GLURP antibodies can inhibit parasite growth in the presence of monocytes via antibody-dependent cellular inhibition (ADCI), and a major parasite-inhibitory region h...
Complete protection against P. berghei malaria upon heterologous prime/boost immunization against circumsporozoite protein employing Salmonella type III secretion system and Bordetella adenylate cyclase toxoid
Tartz, S.; Rüssmann, H.; Kamanová, Jana; Šebo, Peter; Sturm, A.; Heussler, V.; Fleischer, B.; Jacobs, T.
Roč. 26, č. 47 (2008), s. 5935-5943 ISSN 0264-410X R&D Projects: GA MŠk 2B06161 Institutional research plan: CEZ:AV0Z50200510 Keywords : circumsporozoite protein * vaccine * salmonella Subject RIV: EE - Microbiology, Virology Impact factor: 3.298, year: 2008
Berthélemy, Jean-Claude; Thuilliez, Josselin; Doumbo, Ogobara; Gaudart, Jean
In spite of massive efforts to generalize efficient prevention, such as insecticide-treated mosquito nets (ITN) or long-lasting insecticidal nets (LLINs), malaria remains prevalent in many countries and ITN/LLINs are still only used to a limited extent. This study proposes a new model for malaria economic analysis by combining economic epidemiology tools with the literature on poverty traps. A theoretical model of rational protective behaviour in response to malaria is designed, which includes endogenous externalities and disease characteristics. Survey data available for Uganda provide empirical support to the theory of prevalence-elastic protection behaviours, once endogeneity issues related to epidemiology and poverty are solved. Two important conclusions emerge from the model. First, agents increase their protective behaviour when malaria is more prevalent in a society. This is consistent with the literature on "prevalence-elastic behaviour". Second, a 'malaria trap' defined as the result of malaria reinforcing poverty while poverty reduces the ability to deal with malaria can theoretically exist and the conditions of existence of the malaria trap are identified. These results suggest the possible existence of malaria traps, which provides policy implications. Notably, providing ITN/LLINs at subsidized prices is not sufficient. To be efficient an ITN/LLINs dissemination campaigns should include incentive of the very poor for using ITN/LLINs.
Siv, Sovannaroth; Roca-Feltrer, Arantxa; Vinjamuri, Seshu Babu; Bouth, Denis Mey; Lek, Dysoley; Rashid, Mohammad Abdur; By, Ngau Peng; Popovici, Jean; Huy, Rekol; Menard, Didier
The Cambodian National Strategic Plan for Elimination of Malaria aims to move step by step toward elimination of malaria across Cambodia with an initial focus on Plasmodium falciparum malaria before achieving elimination of all forms of malaria, including Plasmodium vivax in 2025. The emergence of artemisinin-resistant P. falciparum in western Cambodia over the last decade has drawn global attention to support the ultimate goal of P. falciparum elimination, whereas the control of P. vivax lags much behind, making the 2025 target gradually less achievable unless greater attention is given to P. vivax elimination in the country. The following review presents in detail the past and current situation regarding P. vivax malaria, activities of the National Malaria Control Program, and interventional measures applied. Constraints and obstacles that can jeopardize our efforts to eliminate this parasite species are discussed. PMID:27708187
Kenthirapalan, S.; Waters, A.P.; Matuschewski, K.; Kooij, T.W.A.
Assigning function to orphan membrane transport proteins and prioritizing candidates for detailed biochemical characterization remain fundamental challenges and are particularly important for medically relevant pathogens, such as malaria parasites. Here we present a comprehensive genetic analysis of
Nygaard, Sanne; Braunstein, Alexander; Malsen, Gareth; Van Dongen, Stijn; Gardner, Paul P.; Krogh, Anders; Otto, Thomas D.; Pain, Arnab; Berriman, Matthew; McAuliffe, Jon; Dermitzakis, Emmanouil T.; Jeffares, Daniel C.
of these genomes. Although evolutionary processes have a significant impact on malaria control, the selective pressures within Plasmodium genomes are poorly understood, particularly in the non-protein-coding portion of the genome. We use evolutionary methods
Full Text Available Salivary gland proteins of the human malaria vector, Anopheles dirus B were determined and analyzed. The amount of salivary gland proteins in mosquitoes aged between 3 - 10 days was approximately 1.08 ± 0.04 µg/female and 0.1 ± 0.05 µg/male. The salivary glands of both sexes displayed the same morphological organization as that of other anopheline mosquitoes. In females, apyrase accumulated in the distal regions, whereas alpha-glucosidase was found in the proximal region of the lateral lobes. This differential distribution of the analyzed enzymes reflects specialization of different regions for sugar and blood feeding. SDS-PAGE analysis revealed that at least seven major proteins were found in the female salivary glands, of which each morphological region contained different major proteins. Similar electrophoretic protein profiles were detected comparing unfed and blood-fed mosquitoes, suggesting that there is no specific protein induced by blood. Two-dimensional polyacrylamide gel analysis showed the most abundant salivary gland protein, with a molecular mass of approximately 35 kilodaltons and an isoelectric point of approximately 4.0. These results provide basic information that would lead to further study on the role of salivary proteins of An. dirus B in disease transmission and hematophagy.Proteínas das glândulas salivares do Anopheles dirus B (Diptera: Culicidae, vetor da malária humana foram determinadas e analisadas. A quantidade de proteínas das glândulas salivares em mosquitos com três a 10 dias de idade foi de aproximadamente 1,08 ± 0,04 µg/ fêmea e de 0,1 ± 0,05 µg/macho. As glândulas salivares de ambos os sexos mostraram organização morfológica semelhante à de outros mosquitos anofelinos. Em fêmeas, apirase acumula-se nas regiões distais, enquanto alfa-glucosidase foi encontrada na região proximal dos lóbulos laterais. Esta distribuição diferencial das enzimas analisadas reflete a especialização de
Wanji, Samuel; Kengne-Ouafo, Arnaud J.; Joan Eyong, Ebanga E.; Kimbi, Helen K.; Tendongfor, Nicholas; Ndamukong-Nyanga, Judith L.; Nana-Djeunga, Hugues C.; Bourguinat, Catherine; Sofeu-Feugaing, David D.; Charvet, Claude L.
The present study analyzed the relationship between the genetic diversity of Plasmodium falciparum and parasitologic/entomologic indices in the Mount Cameroon region by using merozoite surface protein 1 as a genetic marker. Blood samples were collected from asymptomatic children from three altitude zones (high, intermediate, and low). Parasitologic and entomologic indices were determined by microscopy and landing catch mosquito collection/circumsporozoite protein–enzyme-linked immunosorbent a...
Full Text Available Cerebral malaria is one of the fatal complications of Plasmodium falciparum infection. Pathogenesis involves cerebral microangiopathy related to microvascular plugging by infected red blood cells. Conventional imaging with MRI and CT do not reveal anything specific in case of cerebral malaria. Susceptibility weighted imaging, a recent advance in the MRI, is very sensitive to microbleeds related to microangiopathy. Histopathological studies in cerebral malaria have revealed microbleeds in brain parenchyma secondary to microangiopathy. Susceptibility weighted imaging, being exquisitely sensitive to microbleeds may provide additional information and improve the diagnostic accuracy of MRI in cerebral malaria.
Full Text Available Some sensitivity tests of antimalarial drugs had been done by National Institute of Health Research and Development in collaboration with Directorate General of Communicable Disease Control and Environment Health, Naval Medical Research Unit No.2 and Faculty of Medicine University of Indonesia. In-vivo and or in-vitro Plasmodium falciparum multidrug resistance was reported from 11 provinces : Aceh, North Sumatera, Riau, Lampung, West Java, Jakarta (imported case, Central Java, East Kalimantan, South Sulawesi, East Nusa Tenggara and Irian Jaya. Only quinine had a good response for treatment of falciparum malaria resistant to multidrug. R falciparum resistant to mefloquine or halofantrine was found although it was not available in Indonesia yet. Chloroquine prophylaxis using standard dose was still effective in Tanjung Pinang and Central Java. To support the successfulness of treatment in malaria control programme, further studies on alternative antimalaria drugs is needed.
Cuesta Astroz, Yesid; Segura Latorre, Cesar
Malaria is a parasitic disease that has a high impact on public health in developing countries. The sequencing of the plasmodium falciparum genome and the development of proteomics have enabled a breakthrough in understanding the biology of the parasite. Proteomics have allowed to characterize qualitatively and quantitatively the parasite s expression of proteins and has provided information on protein expression under conditions of stress induced by antimalarial. Given the complexity of their life cycle, this takes place in the vertebrate host and mosquito vector. It has proven difficult to characterize the protein expression during each stage throughout the infection process in order to determine the proteome that mediates several metabolic, physiological and energetic processes. Two dimensional electrophoresis, liquid chromatography and mass spectrometry have been useful to assess the effects of antimalarial on parasite protein expression and to characterize the proteomic profile of different p. falciparum stages and organelles. The purpose of this review is to present state of the art tools and advances in proteomics applied to the study of malaria, and to present different experimental strategies used to study the parasite's proteome in order to show the advantages and disadvantages of each one.
Sleebs, Brad E; Lopaticki, Sash; Marapana, Danushka S
, Plasmepsin V (PMV). The PMV gene is refractory to deletion, suggesting it is essential, but definitive proof is lacking. Here, we generated a PEXEL-mimetic inhibitor that potently blocks the activity of PMV isolated from P. falciparum and Plasmodium vivax. Assessment of PMV activity in P. falciparum revealed...... surface, and cytoadherence. The inhibitor killed parasites at the trophozoite stage and knockdown of PMV enhanced sensitivity to the inhibitor, while overexpression of PMV increased resistance. This provides the first direct evidence that PMV activity is essential for protein export in Plasmodium spp....... and for parasite survival in human erythrocytes and validates PMV as an antimalarial drug target....
Pollyanna Stephanie Gomes
Full Text Available Malaria is one of the most life-threatening infectious diseases worldwide. Immunity to malaria is slow and short-lived despite the repeated parasite exposure in endemic areas. Malaria parasites have evolved refined machinery to evade the immune system based on a range of genetic changes that include allelic variation, biomolecular exposure of proteins and intracellular replication. All of these features increase the probability of survival in both mosquitoes and the vertebrate host. Plasmodium species escape from the first immunological trap in its invertebrate vector host, the Anopheles mosquitoes. The parasites have to pass through various immunological barriers within the mosquito such as anti-microbial molecules and the mosquito microbiota in order to achieve successful transmission to the vertebrate host. Within these hosts, Plasmodium species employ various immune evasion strategies during different life cycle stages. Parasite persistence against the vertebrate immune response depends on the balance among virulence factors, pathology, metabolic cost of the host immune response, and the parasites ability to evade the immune response. In this review we discuss the strategies that Plasmodium parasites use to avoid the vertebrate host immune system and how they promote successful infection and transmission.
Presumptive treatment of malaria results in significant overuse of antimalarials. This study compared the diagnostic accuracy of Histidine Rich Protein II and plasmodium lactate dehydrogenase (pLDH)-based Rapid Kits( RDTs)and using expert microscopy as the gold standard for the detection of falciparum and ...
Mockenhaupt, Frank P.; Ehrhardt, Stephan; Eggelte, Teunis A.; Markert, Miriam; Anemana, Sylvester; Otchwemah, Rowland; Bienzle, Ulrich
In 366 Ghanaian children with symptomatic Plasmodium falciparum malaria, low haemoglobin levels and severe anaemia were associated with a high multiplicity of infection (MOI) and with distinct merozoite surface protein alleles. High MOI not only reflects premunition but may also contribute to
CONCLUSION: The relationship between expenditure and use of different vector control depends on the geographic location of respondents. People living in the rural areas spend more to have access to malaria control tools. Location of respondent has a positive effect on expenditures and use of malaria control tools.
In clinical settings, management of malaria cases has primarily been centred on case definition, giving minimal consideration to the asymptomatic individuals who remain a major reservoir since they do not seek care. In malaria endemic areas, infants are likely to remain asymptomatic since they have partial immunity ...
Full Text Available A linkage between presence of Sickle Haemoglobin (HbS and protection from malaria infection and clinical manifestations in certain areas was suspected from early observations and progressively elucidated by more recent studies. Research has confirmed the abovementioned connection, but also clarified how such protection may be abolished by coexistence of sickle cell trait (HbS trait and alpha thalassemia, which may explain the relatively low incidence of HbS trait in the Mediterranean. The mechanisms of such protective effect are now being investigated: factors of genetic, molecular and immunological nature are prominent. As for genetic factors attention is given to the role of the red blood cell (RBC membrane complement regulatory proteins as polymorphisms of these components seem to be associated with resistance to severe malaria; genetic ligands like the Duffy group blood antigen, necessary for erythrocytic invasion, and human protein CD36, a major receptor for P. falciparum-infected RBC‘s, are also under scrutiny: attention is focused also on plasmodium erythrocyte-binding antigens, which bind to RBC surface components. Genome-wide linkage and association studies are now carried out too, in order to identify genes associated with malaria resistance. Only a minor role is attributed to intravascular sickling, phagocytosis and haemolysis, while specific molecular mechanisms are the object of intensive research: among these a decisive role is played by a biochemical sequence, involving activation of haeme oxygenase (HMO-1, whose effect appears mediated by carbon monoxide (CO. A central role in protection from malaria is also played by immunological factors, which may stimulate antibody production to plasmodium antigens in the early years of life; the role of agents like pathogenic CD8 T-cells has been suggested while the effects of molecular actions on the immunity mechanism are presently investigated. It thus appears that protection from
Patience B Tetteh-Quarcoo
Full Text Available Complement receptor-type 1 (CR1, CD35 is the immune-adherence receptor, a complement regulator, and an erythroid receptor for Plasmodium falciparum during merozoite invasion and subsequent rosette formation involving parasitized and non-infected erythrocytes. The non-uniform geographical distribution of Knops blood group CR1 alleles Sl1/2 and McC(a/b may result from selective pressures exerted by differential exposure to infectious hazards. Here, four variant short recombinant versions of CR1 were produced and analyzed, focusing on complement control protein modules (CCPs 15-25 of its ectodomain. These eleven modules encompass a region (CCPs 15-17 key to rosetting, opsonin recognition and complement regulation, as well as the Knops blood group polymorphisms in CCPs 24-25. All four CR1 15-25 variants were monomeric and had similar axial ratios. Modules 21 and 22, despite their double-length inter-modular linker, did not lie side-by-side so as to stabilize a bent-back architecture that would facilitate cooperation between key functional modules and Knops blood group antigens. Indeed, the four CR1 15-25 variants had virtually indistinguishable affinities for immobilized complement fragments C3b (K(D = 0.8-1.1 µM and C4b (K(D = 5.0-5.3 µM. They were all equally good co-factors for factor I-catalysed cleavage of C3b and C4b, and they bound equally within a narrow affinity range, to immobilized C1q. No differences between the variants were observed in assays for inhibition of erythrocyte invasion by P. falciparum or for rosette disruption. Neither differences in complement-regulatory functionality, nor interactions with P. falciparum proteins tested here, appear to have driven the non-uniform geographic distribution of these alleles.
Spottiswoode, Natasha; Armitage, Andrew E; Williams, Andrew R
/SMAD pathway and has been associated with increased hepcidin during inflammation, was upregulated in the livers of Plasmodium berghei infected mice; hepatic activin B was also upregulated at peak parasitemia during infection with Plasmodium chabaudi Concentrations of the closely related protein activin...... are unlikely to stimulate hepcidin upregulation directly. In conclusion, we present evidence that the BMP/SMAD signalling pathway is perturbed in malaria infection, but that activins, although raised in malaria infection, may not have a critical role in hepcidin upregulation in this setting....
Malaria remains one of the highest contributors to the precarious maternal mortality figures in sub-Saharan Africa. At least 6 million women worldwide are at risk of malaria infection in pregnancy. Malaria contributes to at least 10,000 maternal deaths and to at least 200,000 newborn deaths annually. Malaria is a contributor ...
Jakobsen, P H; McKay, V; N'Jie, R
Healthy Gambian children, children with clinical Plasmodium falciparum malaria, and children with asymptomatic P. falciparum infections were studied to investigate whether antitoxic activities may contribute to protection against malarial symptoms. Markers of inflammatory reactions, soluble tumor...... necrosis factor receptor I, and C-reactive protein were found in high concentrations in children with symptomatic P. falciparum malaria compared with levels in children with asymptomatic P. falciparum infections or in healthy children, indicating that inflammatory reactions are induced only in children...... decreased capacity to block induction of LAL activation by P. falciparum exoantigen. The decreased blocking activity was restored in the following dry season, when the children had no clinical malaria. Symptomatic children also had the highest immunoglobulin G (IgG) reactivities to conserved P. falciparum...
Mace, Kimberly E; Arguin, Paul M; Tan, Kathrine R
Malaria in humans is caused by intraerythrocytic protozoa of the genus Plasmodium. These parasites are transmitted by the bite of an infective female Anopheles species mosquito. The majority of malaria infections in the United States occur among persons who have traveled to regions with ongoing malaria transmission. However, malaria is occasionally acquired by persons who have not traveled out of the country through exposure to infected blood products, congenital transmission, laboratory exposure, or local mosquitoborne transmission. Malaria surveillance in the United States is conducted to provide information on its occurrence (e.g., temporal, geographic, and demographic), guide prevention and treatment recommendations for travelers and patients, and facilitate transmission control measures if locally acquired cases are identified. This report summarizes confirmed malaria cases in persons with onset of illness in 2015 and summarizes trends in previous years. Malaria cases diagnosed by blood film microscopy, polymerase chain reaction, or rapid diagnostic tests are reported to local and state health departments by health care providers or laboratory staff members. Case investigations are conducted by local and state health departments, and reports are transmitted to CDC through the National Malaria Surveillance System (NMSS), the National Notifiable Diseases Surveillance System (NNDSS), or direct CDC consultations. CDC reference laboratories provide diagnostic assistance and conduct antimalarial drug resistance marker testing on blood samples submitted by health care providers or local or state health departments. This report summarizes data from the integration of all NMSS and NNDSS cases, CDC reference laboratory reports, and CDC clinical consultations. CDC received reports of 1,517 confirmed malaria cases, including one congenital case, with an onset of symptoms in 2015 among persons who received their diagnoses in the United States. Although the number of
Plasmodium life cycle . (a) Sporozoites enter the liver lobule either via the portal venule or the hepatic artery, and arrest by binding to the sinusoidal...scope of the problem Malaria is caused by the protozoan genus Plasmodium and is responsible for 700 000 to 1 000 000 deaths per year in tropical...circumsporozoite protein (CS protein)] of the Plasmodium falciparum (Pf) sporozoite. RTS,S has the potential to provide a significant health benefit if the
Lalremruata, Albert; Magris, Magda; Vivas-Martínez, Sarai; Koehler, Maike; Esen, Meral; Kempaiah, Prakasha; Jeyaraj, Sankarganesh; Perkins, Douglas Jay; Mordmüller, Benjamin; Metzger, Wolfram G
The quartan malaria parasite Plasmodium malariae is the widest spread and best adapted human malaria parasite. The simian Plasmodium brasilianum causes quartan fever in New World monkeys and resembles P. malariae morphologically. Since the genetics of the two parasites are nearly identical, differing only in a range of mutations expected within a species, it has long been speculated that the two are the same. However, no naturally acquired infection with parasites termed as P. brasilianum has been found in humans until now. We investigated malaria cases from remote Yanomami indigenous communities of the Venezuelan Amazon and analyzed the genes coding for the circumsporozoite protein (CSP) and the small subunit of ribosomes (18S) by species-specific PCR and capillary based-DNA sequencing. Based on 18S rRNA gene sequencing, we identified 12 patients harboring malaria parasites which were 100% identical with P. brasilianum isolated from the monkey, Alouatta seniculus. Translated amino acid sequences of the CS protein gene showed identical immunodominant repeat units between quartan malaria parasites isolated from both humans and monkeys. This study reports, for the first time, naturally acquired infections in humans with parasites termed as P. brasilianum. We conclude that quartan malaria parasites are easily exchanged between humans and monkeys in Latin America. We hypothesize a lack of host specificity in mammalian hosts and consider quartan malaria to be a true anthropozoonosis. Since the name P. brasilianum suggests a malaria species distinct from P. malariae, we propose that P. brasilianum should have a nomenclatorial revision in case further research confirms our findings. The expansive reservoir of mammalian hosts discriminates quartan malaria from other Plasmodium spp. and requires particular research efforts.
Bygbjerg, Ib Christian
The literature on fake medicaments is sparse, even if approximately 15% of all medicaments are fake, a figure that for antimalarials in particular reaches 50% in parts of Africa and Asia. Sub-standard and fake medicines deplete the public's confidence in health systems, health professionals and in the pharmaceutical industry - and increase the risk that resistance develops. For a traveller coming from a rich Western country, choosing to buy e.g. preventive antimalarials over the internet or in poor malaria-endemic areas, the consequences may be fatal. International trade-, control- and police-collaboration is needed to manage the problem, as is the fight against poverty and poor governance.
Biot, Christophe; Dive, Daniel
This chapter summarizes recent developments in the design, synthesis, and structure-activity relationship studies of organometallic antimalarials. It begins with a general introduction to malaria and the biology of the parasite Plasmodium falciparum, with a focus on the heme detoxification system. Then, a number of metal complexes from the literature are reported for their antiplasmodial activity. The second half of the chapter deals with the serendipitous discovery of ferroquine, its mechanism(s) of action, and the failure to induce a resistance. Last, but not least, we suggest that the bioorganometallic approach offers the potential for the design of novel therapeutic agents.
Acquah, Festus K; Obboh, Evans K; Asare, Kwame; Boampong, Johnson N; Nuvor, Samuel Victor; Singh, Susheel K; Theisen, Michael; Williamson, Kim C; Amoah, Linda Eva
Recent advances in malaria control efforts have led to an increased number of national malaria control programmes implementing pre-elimination measures and demonstrated the need to develop new tools to track and control malaria transmission. Key to understanding transmission is monitoring the prevalence and immune response against the sexual stages of the parasite, known as gametocytes, which are responsible for transmission. Sexual-stage specific antigens, Pfs230 and Pfs48/45, have been identified and shown to be targets for transmission blocking antibodies, but they have been difficult to produce recombinantly in the absence of a fusion partner. Regions of Pfs48/45 and Pfs230 known to contain transmission blocking epitopes, 6C and C0, respectively, were produced in a Lactococcus lactis expression system and used in enzyme linked immunosorbent assays to determine the seroreactivity of 95 malaria patients living in the Central Region of Ghana. Pfs48/45.6C and Pfs230.C0 were successfully produced in L. lactis in the absence of a fusion partner using a simplified purification scheme. Seroprevalence for L. lactis-produced Pfs48/45.6C and Pfs230.C0 in the study population was 74.7 and 72.8%, respectively. A significant age-dependent increase in antibody titers was observed, which suggests a vaccine targeting these antigens could be boosted during a natural infection in the field.
... and malaria is common in sub-Saharan Africa, and is a complex phenomenon. ... iron status and malaria incidence among children in a high malaria ... seasonally as cash crops. ... Children were followed for presence of malaria parasites by.
Jakobsen, P H; Bate, C A; Taverne, J
In this review the old concept of severe malaria as a toxic disease is re-examined in the light of recent discoveries in the field of cytokines. Animal studies suggest that the induction of TNF by parasite-derived molecules may be partly responsible for cerebral malaria and anemia, while...... hypoglycaemia may be due to direct effects of similar molecules on glucose metabolism. These molecules appear to be phospholipids and we suggest that when fully characterized they might form the basis of antitoxic therapy for malaria....
Zenz, W; Trop, M; Kollaritsch, H; Reinthaler, F
Increasing tourism and growing numbers of immigrants from malaria-endemic countries are leading to a higher importation rate of rare tropical disorders in European countries. We describe, to the best of our knowledge, the first case of connatal malaria in Austria. The patient is the first child of a 24 year old mother who was born in Ghana and immigrated to Austria one and a half years before delivery. She did not stay in an endemic region during this period and did not show fever or any other signs of malaria. The boy was healthy for the first six weeks of his life. In the 8th week of life he was admitted to our hospital due to persistent fever of unknown origin. On physical examination he showed only mild splenomegaly. Routine laboratory testing revealed mild hemolytic anemia with a hemoglobin value of 8.3 g/l. In the blood smear Plasmodium falciparum and Plasmodium malariae were detected. Oral therapy with quinine hydrochloride was successful and blood smears became negative for Plasmodia within 6 days. This case shows that congenital malaria can occur in children of clinically healthy women who were born in malaria-endemic areas even one and a half year after they have immigrated to non-endemic regions.
Limbach, Keith; Stefaniak, Maureen; Chen, Ping; Patterson, Noelle B; Liao, Grant; Weng, Shaojie; Krepkiy, Svetlana; Ekberg, Greg; Torano, Holly; Ettyreddy, Damodar; Gowda, Kalpana; Sonawane, Sharvari; Belmonte, Arnel; Abot, Esteban; Sedegah, Martha; Hollingdale, Michael R; Moormann, Ann; Vulule, John; Villasante, Eileen; Richie, Thomas L; Brough, Douglas E; Bruder, Joseph T
A DNA-human Ad5 (HuAd5) prime-boost malaria vaccine has been shown to protect volunteers against a controlled human malaria infection. The potency of this vaccine, however, appeared to be affected by the presence of pre-existing immunity against the HuAd5 vector. Since HuAd5 seroprevalence is very high in malaria-endemic areas of the world, HuAd5 may not be the most appropriate malaria vaccine vector. This report describes the evaluation of the seroprevalence, immunogenicity and efficacy of three newly identified gorilla adenoviruses, GC44, GC45 and GC46, as potential malaria vaccine vectors. The seroprevalence of GC44, GC45 and GC46 is very low, and the three vectors are not efficiently neutralized by human sera from Kenya and Ghana, two countries where malaria is endemic. In mice, a single administration of GC44, GC45 and GC46 vectors expressing a murine malaria gene, Plasmodium yoelii circumsporozoite protein (PyCSP), induced robust PyCSP-specific T cell and antibody responses that were at least as high as a comparable HuAd5-PyCSP vector. Efficacy studies in a murine malaria model indicated that a prime-boost regimen with DNA-PyCSP and GC-PyCSP vectors can protect mice against a malaria challenge. Moreover, these studies indicated that a DNA-GC46-PyCSP vaccine regimen was significantly more efficacious than a DNA-HuAd5-PyCSP regimen. These data suggest that these gorilla-based adenovectors have key performance characteristics for an effective malaria vaccine. The superior performance of GC46 over HuAd5 highlights its potential for clinical development.
prevalence of malaria is a major selective agent in- ... century before Darwin put forward the Theory of Natural ... A. C. Allison, a former research student of the Anatomy ... A review of all available ... However, they both draw attention to the.
Gockchinar, T; Kalipsi, S
Geographically, Turkey is situated in an area where malaria is very risky. The climatic conditions in the region are suitable for the malaria vector to proliferate. Due to agricultural infrastructural changes, GAP and other similar projects, insufficient environmental conditions, urbanization, national and international population moves, are a key to manage malaria control activities. It is estimated that malaria will be a potential danger for Turkey in the forthcoming years. The disease is located largely in south-eastern Anatolia. The Diyarbakir, Batman, Sanliurfa, Siirt, and Mardin districts are the most affected areas. In western districts, like Aydin and Manisa, an increase in the number of indigenous cases can be observed from time to time. This is due to workers moving from malaria districts to western parts to final work. Since these workers cannot be controlled, the population living in these regions get infected from indigenous cases. There were 84,345 malaria cases in 1994 and 82,096 in 1995, they decreased to 60,884 in 1996 and numbered 35,456 in 1997. They accounted for 36,842 and 20,963 in 1998 and 1999, respectively. In Turkey there are almost all cases of P. vivax malaria. There are also P. vivax and P. falciparum malaria cases coming from other countries: There were 321 P. vivax cases, including 2 P. falciparum ones, arriving to Turkey from Iraq in 1995. The P. vivax malaria cases accounted for 229 in 1996, and 67, cases P. vivax including 12 P. falciparum cases, in 1997, and 4 P. vivax cases in 1998 that came from that country. One P. vivax case entered Turkey from Georgia in 1998. The cause of higher incidence of P. vivax cases in 1995, it decreasing in 1999, is the lack of border controls over workers coming to Turkey. The other internationally imported cases are from Syria, Sudan, Pakistan, Afghanistan, Nigeria, India, Azerbaijan, Malaysia, Ghana, Indonesia, Yemen. Our examinations have shown that none of these internationally imported cases
Full Text Available BACKGROUND: Several clinical forms of malaria such as chronic carriage, gestational malaria or hyper-reactive malarial splenomegaly may follow a cryptic evolution with afebrile chronic fatigue sometimes accompanied by anemia and/or splenomegaly. Conventional parasitological tests are often negative or not performed, and severe complications may occur. Extensive explorations of these conditions often include the search for antinuclear autoantibodies (ANA. METHODS: We analysed fluorescence patterns in the ANA test in patients with either chronic cryptic or acute symptomatic malaria, then conducted a one-year prospective study at a single hospital on all available sera drawn for ANA detections. We then identified autoantibodies differentially expressed in malaria patients and in controls using human protein microarray. RESULTS: We uncovered and defined a new, malaria-related, nucleo-cytoplasmic ANA pattern displaying the specific association of a nuclear speckled pattern with diffuse cytoplasmic perinuclearly-enhanced fluorescence. In the one-year prospective analysis, 79% of sera displaying this new nucleo-cytoplasmic fluorescence were from patients with malaria. This specific pattern, not seen in other parasitic diseases, allowed a timely reorientation of the diagnosis toward malaria. To assess if the autoantibody immune response was due to autoreactivity or molecular mimicry we isolated 42 autoantigens, targets of malarial autoantibodies. BLAST analysis indicated that 23 of recognized autoantigens were homologous to plasmodial proteins suggesting autoimmune responses directly driven by the plasmodial infection. CONCLUSION: In patients with malaria in whom parasitological tests have not been performed recognition of this new, malaria-related fluorescence pattern on the ANA test is highly suggestive of the diagnosis and triggers immediate, easy confirmation and adapted therapy.
Hede, Marianne Smedegaard; Fjelstrup, Søren; Knudsen, Birgitta R.
In the field of malaria diagnosis much effort is put into the development of faster and easier alternatives to the gold standard, blood smear microscopy. Nucleic acid amplification based techniques pose some of the most promising upcoming diagnostic tools due to their potential for high sensitivity......, robustness and user-friendliness. In the current review, we will discuss some of the different DNA-based sensor systems under development for the diagnosis of malaria....
Margaret J Mackinnon
Full Text Available While many individual genes have been identified that confer protection against malaria, the overall impact of host genetics on malarial risk remains unknown.We have used pedigree-based genetic variance component analysis to determine the relative contributions of genetic and other factors to the variability in incidence of malaria and other infectious diseases in two cohorts of children living on the coast of Kenya. In the first, we monitored the incidence of mild clinical malaria and other febrile diseases through active surveillance of 640 children 10 y old or younger, living in 77 different households for an average of 2.7 y. In the second, we recorded hospital admissions with malaria and other infectious diseases in a birth cohort of 2,914 children for an average of 4.1 y. Mean annual incidence rates for mild and hospital-admitted malaria were 1.6 and 0.054 episodes per person per year, respectively. Twenty-four percent and 25% of the total variation in these outcomes was explained by additively acting host genes, and household explained a further 29% and 14%, respectively. The haemoglobin S gene explained only 2% of the total variation. For nonmalarial infections, additive genetics explained 39% and 13% of the variability in fevers and hospital-admitted infections, while household explained a further 9% and 30%, respectively.Genetic and unidentified household factors each accounted for around one quarter of the total variability in malaria incidence in our study population. The genetic effect was well beyond that explained by the anticipated effects of the haemoglobinopathies alone, suggesting the existence of many protective genes, each individually resulting in small population effects. While studying these genes may well provide insights into pathogenesis and resistance in human malaria, identifying and tackling the household effects must be the more efficient route to reducing the burden of disease in malaria-endemic areas.
Full Text Available BACKGROUND: While many individual genes have been identified that confer protection against malaria, the overall impact of host genetics on malarial risk remains unknown. METHODS AND FINDINGS: We have used pedigree-based genetic variance component analysis to determine the relative contributions of genetic and other factors to the variability in incidence of malaria and other infectious diseases in two cohorts of children living on the coast of Kenya. In the first, we monitored the incidence of mild clinical malaria and other febrile diseases through active surveillance of 640 children 10 y old or younger, living in 77 different households for an average of 2.7 y. In the second, we recorded hospital admissions with malaria and other infectious diseases in a birth cohort of 2,914 children for an average of 4.1 y. Mean annual incidence rates for mild and hospital-admitted malaria were 1.6 and 0.054 episodes per person per year, respectively. Twenty-four percent and 25% of the total variation in these outcomes was explained by additively acting host genes, and household explained a further 29% and 14%, respectively. The haemoglobin S gene explained only 2% of the total variation. For nonmalarial infections, additive genetics explained 39% and 13% of the variability in fevers and hospital-admitted infections, while household explained a further 9% and 30%, respectively. CONCLUSION: Genetic and unidentified household factors each accounted for around one quarter of the total variability in malaria incidence in our study population. The genetic effect was well beyond that explained by the anticipated effects of the haemoglobinopathies alone, suggesting the existence of many protective genes, each individually resulting in small population effects. While studying these genes may well provide insights into pathogenesis and resistance in human malaria, identifying and tackling the household effects must be the more efficient route to reducing the burden
Clausen, Thomas Mandel; Pereira, Marina Ayres; Al Nakouzi, Nader; Oo, Htoo Zarni; Agerbæk, Mette Ø; Lee, Sherry; Ørum-Madsen, Maj Sofie; Christensen, Anders Riis; El-Naggar, Amal; Grandgenett, Paul M.; Grem, Jean L.; Hollingsworth, Michael A.; Holst, Peter J.; Theander, Thor; Sorensen, Poul H.; Daugaard, Mads; Salanti, Ali
Many tumors express proteoglycans modified with oncofetal chondroitin sulfate glycosaminoglycan chains (ofCS), which are normally restricted to the placenta. However, the role of ofCS in cancer is largely unknown. The function of ofCS in cancer was analyzed using the recombinant ofCS-binding VAR2CSA protein (rVAR2) derived from the malaria parasite, Plasmodium falciparum. We demonstrate that ofCS plays a key role in tumor cell motility by affecting canonical integrin signaling pathways. Binding of rVAR2 to tumor cells inhibited the interaction of cells with extracellular matrix (ECM) components, which correlated with decreased phosphorylation of Src kinase. Moreover, rVAR2 binding decreased migration, invasion and anchorage-independent growth of tumor cells in vitro. Mass spectrometry of ofCS-modified proteoglycan complexes affinity purified from tumor cell lines on rVAR2 columns, revealed an overrepresentation of proteins involved in cell motility and integrin signaling, such as integrin β1 (ITGB1) and integrin α4 (ITGA4). Saturating concentrations of rVAR2 inhibited downstream integrin signaling, which was mimicked by knockdown of the core CS synthesis enzymes Beta-1,3-Glucuronyltransferase 1 (B3GAT1) and Chondroitin Sulfate N-Acetylgalactosaminyltransferase 1 (CSGALNACT1). The ofCS modification was highly expressed in both human and murine metastatic lesions in situ and pre-incubation or early intravenous treatment of tumor cells with rVAR2 inhibited seeding and spreading of tumor cells in mice. This was associated with a significant increase in survival of the animals. These data functionally link ofCS modifications with cancer cell motility and further highlights ofCS as a novel therapeutic cancer target. Implications The cancer specific expression of oncofetal chondroitin sulfate aids in metastatic phenotypes and is a candidate target for therapy. PMID:27655130
Oliveira-Ferreira, Joseli; Lacerda, Marcus V G; Brasil, Patrícia; Ladislau, José L B; Tauil, Pedro L; Daniel-Ribeiro, Cláudio Tadeu
Malaria is still a major public health problem in Brazil, with approximately 306,000 registered cases in 2009, but it is estimated that in the early 1940s, around six million cases of malaria occurred each year. As a result of the fight against the disease, the number of malaria cases decreased over the years and the smallest numbers of cases to-date were recorded in the 1960s. From the mid-1960s onwards, Brazil underwent a rapid and disorganized settlement process in the Amazon and this migratory movement led to a progressive increase in the number of reported cases. Although the main mosquito vector (Anopheles darlingi) is present in about 80% of the country, currently the incidence of malaria in Brazil is almost exclusively (99,8% of the cases) restricted to the region of the Amazon Basin, where a number of combined factors favors disease transmission and impair the use of standard control procedures. Plasmodium vivax accounts for 83,7% of registered cases, while Plasmodium falciparum is responsible for 16,3% and Plasmodium malariae is seldom observed. Although vivax malaria is thought to cause little mortality, compared to falciparum malaria, it accounts for much of the morbidity and for huge burdens on the prosperity of endemic communities. However, in the last few years a pattern of unusual clinical complications with fatal cases associated with P. vivax have been reported in Brazil and this is a matter of concern for Brazilian malariologists. In addition, the emergence of P. vivax strains resistant to chloroquine in some reports needs to be further investigated. In contrast, asymptomatic infection by P. falciparum and P. vivax has been detected in epidemiological studies in the states of Rondonia and Amazonas, indicating probably a pattern of clinical immunity in both autochthonous and migrant populations. Seropidemiological studies investigating the type of immune responses elicited in naturally-exposed populations to several malaria vaccine candidates in
Full Text Available Abstract Malaria is still a major public health problem in Brazil, with approximately 306 000 registered cases in 2009, but it is estimated that in the early 1940s, around six million cases of malaria occurred each year. As a result of the fight against the disease, the number of malaria cases decreased over the years and the smallest numbers of cases to-date were recorded in the 1960s. From the mid-1960s onwards, Brazil underwent a rapid and disorganized settlement process in the Amazon and this migratory movement led to a progressive increase in the number of reported cases. Although the main mosquito vector (Anopheles darlingi is present in about 80% of the country, currently the incidence of malaria in Brazil is almost exclusively (99,8% of the cases restricted to the region of the Amazon Basin, where a number of combined factors favors disease transmission and impair the use of standard control procedures. Plasmodium vivax accounts for 83,7% of registered cases, while Plasmodium falciparum is responsible for 16,3% and Plasmodium malariae is seldom observed. Although vivax malaria is thought to cause little mortality, compared to falciparum malaria, it accounts for much of the morbidity and for huge burdens on the prosperity of endemic communities. However, in the last few years a pattern of unusual clinical complications with fatal cases associated with P. vivax have been reported in Brazil and this is a matter of concern for Brazilian malariologists. In addition, the emergence of P. vivax strains resistant to chloroquine in some reports needs to be further investigated. In contrast, asymptomatic infection by P. falciparum and P. vivax has been detected in epidemiological studies in the states of Rondonia and Amazonas, indicating probably a pattern of clinical immunity in both autochthonous and migrant populations. Seropidemiological studies investigating the type of immune responses elicited in naturally-exposed populations to several
The objective of this study was to describe the epidemiology of imported malaria in Poland in 2010 in comparison to previous years. The study included malaria cases that were collected and registered by the State Sanitary Inspection in 2010 in Poland. Data reported was verified, processed and published by National Institute of Public Health - National Institute of Hygiene. All cases were laboratory confirmed by blood film, polymerase chain reaction or rapid diagnostic tests outlined by the EU case definition. Differences in the distribution of demographic, parasitological and clinical characteristics, and incidence were analyzed. In 2010, a total of 35 confirmed malaria cases were notified in Poland, 13 more than 2009. All cases were imported, 49% from Africa, including 1 case with relapsing malaria caused by P. vivax and 2 cases of recrudescence falciparum malaria following failure of treatment. The number of cases acquired in Asia (37% of the total), mainly from India and Indonesia, was significantly higher than observed in previous years. Among cases with species-specific diagnosis 19 (63%) were caused by P. falciparum, 9 (30%) by P. vivax, one by P. ovale and one by P. malariae. The median age of all cases was 42 years (range 9 months to 71 years), males comprised 69% of patients, females 31%, three patients were Indian citizens temporarily in Poland. Common reasons for travel to endemic countries were tourism (57%), work-related visits (37%), one person visited family and in one case the reason for travel was unknown. Sixteen travelers took chemoprophylaxis, but only three of them appropriately (adherence to the recommended drug regimen, continuation upon return and use of appropriate medicines). In 2010, there were no deaths due to malaria and clinical course of disease was severe in 7 cases. When compared with 2009, there was a marked increase in the number of imported malaria cases in Poland, however the total number of notified cases remained low. Serious
Bélard, Sabine; Issifou, Saadou; Hounkpatin, Aurore B
GMZ2 is a fusion protein of Plasmodium falciparum merozoite surface protein 3 (MSP3) and glutamate rich protein (GLURP) that mediates an immune response against the blood stage of the parasite. Two previous phase I clinical trials, one in naïve European adults and one in malaria-exposed Gabonese ...... adults showed that GMZ2 was well tolerated and immunogenic. Here, we present data on safety and immunogenicity of GMZ2 in one to five year old Gabonese children, a target population for future malaria vaccine efficacy trials....
White Nicholas J
Full Text Available Abstract Background Facilitation of endogenous neuroprotective pathways, such as the erythropoietin (Epo pathway, has been proposed as adjuvant treatment strategies in cerebral malaria. Whether different endogenous protein expression levels of Epo or differences in the abundance of its receptor components could account for the extent of structural neuropathological changes or neurological complications in adults with severe malaria was investigated. Methods High sensitivity immunohistochemistry was used to assess the frequency, distribution and concordance of Epo and components of its homodimeric and heteromeric receptors, Epo receptor and CD131, within the brainstem of adults who died of severe malaria. The following relationships with Epo and its receptor components were also defined: (i sequestration and indicators of hypoxia; (ii vascular damage in the form of plasma protein leakage and haemorrhage; (iii clinical complications and neuropathological features of severe malaria disease. Brainstems of patients dying in the UK from unrelated non-infectious causes were examined for comparison. Results The incidence of endogenous Epo in parenchymal brain cells did not greatly differ between severe malaria and non-neurological UK controls at the time of death. However, EpoR and CD131 labelling of neurons was greater in severe malaria compared with non-neurological controls (P = .009. EpoR labelling of vessels was positively correlated with admission peripheral parasite count (P = .01 and cerebral sequestration (P P = .001. There were no significant correlations with indicators of vascular damage, neuronal chromatolysis, axonal swelling or vital organ failure. Conclusion Cells within the brainstem of severe malaria patients showed protein expression of Epo and its receptor components. However, the incidence of endogeneous expression did not reflect protection from vascular or neuronal injury, and/or clinical manifestations, such as coma. These
Petersen, E; Høgh, B; Dziegiel, M
, and a synthetic peptide (EENV)6 representing the C-terminal repeats from Pf155/RESA, were investigated longitudinally in 13 children and 7 adults living under conditions of continuous, intense malaria transmission. Some subjects did not recognize the antigens after malaria infection, and in subjects recognizing...... elicited by natural malaria infection in previously primed donors....
Abdulla, S.; Agre, P.; Alonso, P.L.; Arevalo-Herrera, M.; Bassat, Q.; Binka, F.; Chitnis, C.; Corradin, G.; Cowman, A. F.; Culpepper, J.; Portillo, H. del; Dinglasan, R.R.; Duffy, P.; Gargallo, D.; Greenwood, B.; Guinovart, C.; Hall, B.F.; Herrera, S.; Hoffman, S.; Lanzavecchia, A.; Leroy, O.; Levine, M.M.; Loucq, C.; Mendis, K.; Milman, J.; Moorthy, V.S.; Pleuschke, G.; Plowe, C.V.; Reed, S.; Sauerwein, R.W.; Saul, A.; Schofield, L.; Sinden, R.R.; Stubbs, J.; Villafana, T.; Wirth, D.; Yadav, P.; Ballou, R.; Brown, G.; Birkett, A.; Brandt, W.; Brooks, A.; Carter, T.; Golden, A.; Lee, C.; Nunes, J.; Puijalon, O.; Raphael, T.; Richards, H.; Warren, C.; Woods, C.
Vaccines could be a crucial component of efforts to eradicate malaria. Current attempts to develop malaria vaccines are primarily focused on Plasmodium falciparum and are directed towards reducing morbidity and mortality. Continued support for these efforts is essential, but if
Dec 15, 2009 ... 6Department of Parasitology, School of Medical Laboratory ... Malaria prevalence studies had been undertaken in many parts of Nigeria but there is probably no data ..... within the limits of the malaria prevalence rate reports in.
Malaria is the world's most common parasitic infection, affecting more thatn 500 million people annually and killing more than 1 million. In order to help combat malaria, CERN has launched a grid computing effort (1 page)
Malaria prevention is increasingly insecticide based. Dr. John Gimnig, an entomologist with the Division of Parasitic Diseases, CDC, discusses evidence that mosquito resistance to insecticides, which is measured in the laboratory, could compromise malaria prevention in the field.
regard to tourism, within an area of ~100 000 km2. ... Unfortunately, international funding for .... carriers, whether symptomatic or asymptomatic, to interrupt malaria ... education of healthcare workers on malaria diagnosis and treatment.
Feb 2, 2000 ... randomisation produced comparable intervention and comparison groups with balanced characteristics. Specific results of the baseline studies are presented in the companion paper. ... strategies for protecting pregnant women against malaria. ..... from malaria vaccine trial conducted among Tanzanian.
Chibueze Peter Ihekwereme
Full Text Available Malaria has a negative impact on health and social and economic life of residents of endemic countries. The ultimate goals of designing new treatment for malaria are to prevent clinical infection, reduce morbidity, and decrease mortality. There are great advances in the understanding of the parasite-host interaction through studies by various scientists. In some of these studies, attempts were made to evaluate the roles of malaria pigment or toxins in the pathogenesis of malaria. Hemozoin is a key metabolite associated with severe malaria anemia (SMA, immunosuppression, and cytokine dysfunction. Targeting of this pigment may be necessary in the design of new therapeutic products against malaria. In this review, the roles of hemozoin in the morbidity and mortality of malaria are highlighted as an essential target in the quest for effective control of clinical malaria.
Moiz, Bushra; Arshad, Haroon Muhammad; Raheem, Ahmed; Hayat, Hasan; Karim Ghanchi, Najia; Beg, M Asim
Pakistan has an estimated annual burden of 1.5 million malaria cases. The current situation calls for an effective malaria control and eradication programme in this country. Currently, primaquine is an attractive option for eliminating reservoirs of Plasmodium vivax hypnozoites and killing gametocytes of Plasmodium falciparum. However, this drug causes haemolysis in individuals who are glucose-6-phosphate (G6PD) deficient. It is important to map G6PD deficiency and malaria distribution in Pakistan to design an effective malaria eradication regimen. Frequency of G6PD deficiency (G6PDd) in malaria patients has not been reported from Pakistan in any meaningful way. The purpose of this study was to evaluate the frequency of G6PD c.563C>T (G6PD Mediterranean) in male individuals with and without falciparum malaria. Two hundred and ten archived DNA samples from males (110 from falciparum malaria patients and 100 from healthy individuals) were utilized in this study. Healthy blood donors were selected based on stringent pre-defined criteria. Patients were confirmed for malaria parasites on microscopy and or immune chromatographic assay detecting P. falciparum histidine-rich protein 2. Parasitaemia was also computed. DNA samples were tested for G6PD c.563C>T mutation through PCR-RFLP according to the previously defined protocol and its allelic frequency was computed. G6PD c.563C>T was observed in four of 110 patients with falciparum malaria and in two of 100 healthy donors. Mean (± SD) haemoglobin, median (IQR) platelet and median (IQR) parasite count in G6PD-deficient malaria-patients were 8.9 ± 0.9 g/dL, 124 × 109/L (IQR 32, 171) and 57,920/μL of blood (IQR 12,920, 540,000) respectively. Cumulative allelic frequency for G6PD 563c.C>T was 0.0285 detected in 6 of 210 X-chromosomes in Southern Pakistan. Frequency for this G6PD allele was 0.0364 in malaria-patients and 0.0200 in healthy individuals. Large studies including females are needed to elucidate the true
Sharman, Joanna L; Gerloff, Dietlind L
The Malaria Genome Exploration Tool (MaGnET) is a software tool enabling intuitive 'exploration-style' visualization of functional genomics data relating to the malaria parasite, Plasmodium falciparum. MaGnET provides innovative integrated graphic displays for different datasets, including genomic location of genes, mRNA expression data, protein-protein interactions and more. Any selection of genes to explore made by the user is easily carried over between the different viewers for different datasets, and can be changed interactively at any point (without returning to a search). Free online use (Java Web Start) or download (Java application archive and MySQL database; requires local MySQL installation) at http://malariagenomeexplorer.org email@example.com or firstname.lastname@example.org Supplementary data are available at Bioinformatics online.
Klug, Dennis; Frischknecht, Friedrich
Malaria is transmitted when an infected Anopheles mosquito deposits Plasmodium sporozoites in the skin during a bite. Sporozoites are formed within oocysts at the mosquito midgut wall and are released into the hemolymph, from where they invade the salivary glands and are subsequently transmitted to the vertebrate host. We found that a thrombospondin-repeat containing sporozoite-specific protein named thrombospondin-releated protein 1 (TRP1) is important for oocyst egress and salivary gland invasion, and hence for the transmission of malaria. We imaged the release of sporozoites from oocysts in situ, which was preceded by active motility. Parasites lacking TRP1 failed to migrate within oocysts and did not egress, suggesting that TRP1 is a vital component of the events that precede intra-oocyst motility and subsequently sporozoite egress and salivary gland invasion. DOI: http://dx.doi.org/10.7554/eLife.19157.001 PMID:28115054
Lalloo, David G; Shingadia, Delane; Bell, David J; Beeching, Nicholas J; Whitty, Christopher J M; Chiodini, Peter L
1.Malaria is the tropical disease most commonly imported into the UK, with 1300-1800 cases reported each year, and 2-11 deaths. 2. Approximately three quarters of reported malaria cases in the UK are caused by Plasmodium falciparum, which is capable of invading a high proportion of red blood cells and rapidly leading to severe or life-threatening multi-organ disease. 3. Most non-falciparum malaria cases are caused by Plasmodium vivax; a few cases are caused by the other species of plasmodium: Plasmodium ovale, Plasmodium malariae or Plasmodium knowlesi. 4. Mixed infections with more than one species of parasite can occur; they commonly involve P. falciparum with the attendant risks of severe malaria. 5. There are no typical clinical features of malaria; even fever is not invariably present. Malaria in children (and sometimes in adults) may present with misleading symptoms such as gastrointestinal features, sore throat or lower respiratory complaints. 6. A diagnosis of malaria must always be sought in a feverish or sick child or adult who has visited malaria-endemic areas. Specific country information on malaria can be found at http://travelhealthpro.org.uk/. P. falciparum infection rarely presents more than six months after exposure but presentation of other species can occur more than a year after exposure. 7. Management of malaria depends on awareness of the diagnosis and on performing the correct diagnostic tests: the diagnosis cannot be excluded until more than one blood specimen has been examined. Other travel related infections, especially viral haemorrhagic fevers, should also be considered. 8. The optimum diagnostic procedure is examination of thick and thin blood films by an expert to detect and speciate the malarial parasites. P. falciparum and P. vivax (depending upon the product) malaria can be diagnosed almost as accurately using rapid diagnostic tests (RDTs) which detect plasmodial antigens. RDTs for other Plasmodium species are not as reliable. 9
Jun 29, 1974 ... Malaria admissions. Cerebral malaria ... Cerebral signs. Haemoglobin below 10 g/100 ml (not all tested). Enlarged tender liver or jaundice, or both ... articl~ by H. Smitskamp and F. H. Wolthuis entitled 'New concepts in treatment of malaria with malignant tertian cerebral involvement' which appeared in the ...
Africa among the human population. Determination of risk of malaria transmission requires quick and accurate methods of identification of Anopheles mosquitoes especially when targeting vector control. (Maxwell, et al., 2003). Anopheles mosquito transmits malaria. The most important vectors of malaria are members of.
An audit of all malaria deaths that occurred at Manguzi Hospital between 1 October 1998 to 30 September 1999 was performed. There were 41 deaths from malaria in this time period, which was many more than for the previous three years. The most common causes of death were cerebral malaria, pulmonary oedema, ...
control of malaria in the African Subregion during pregnancy has been recommended by the World Health Organization (WHO). These include intermittent preventive treatment (IPT), use of insecticide treated nets (ITNs) and access to effective case management for malaria illness and anemia. Keywords: malaria in ...
The article surveys the expansion of the malaria risk zones with increasing temperatures, change in climate and habitat alterations. Factors such as the living conditions for various malaria parasites, climatic changes, immunity and drug resistance are studied. It is evident that the greenhouse effects contribute to the expanding malaria risk zones
Background: Malaria, earlier considered rare in neonates, has been reported with increasing frequency in the last decade. Neonatal malaria diagnosis is challenging because the clinical features are non-specific, variable and also overlap with bacterial infection. Aim: To determine the prevalence of neonatal malaria and ...
The burden of malaria and its associated problems in pregnancy can be reduced by the use of different malaria preventive measures. This study was conducted to determine the comparative effectiveness of three different malaria preventive measures on populations of parturient in Abeokuta, Ogun State, Nigeria.
Nygaard, Sanne; Braunstein, Alexander; Malsen, Gareth
Plasmodium parasites, the causal agents of malaria, result in more than 1 million deaths annually. Plasmodium are unicellular eukaryotes with small ~23 Mb genomes encoding ~5200 protein-coding genes. The protein-coding genes comprise about half of these genomes. Although evolutionary processes ha...
Full Text Available Malaria is a disease caused by intercellular obligate protozoa genus of Plasmodium which is a parasite carried by female Anopheles mosquito. One of them is Anopheles barbirostris. Research in several places already proved that Anopheles barbirostris acts as a vector of malaria. One case that occurred in Cineam district, Tasikmalaya regency showed that Anopheles barbirostris is suspected as vector of malaria. This is proven through a research on the relationship between Anopheles barbirostris with malaria. Data was taken from the larvae and adult mosquitoes captured around Cineam village, Tasikmalaya. The observation was done in the open field and laboratory. Data and identification by pictorial key for female Anopheles showed that the population of Anopheles barbirostris was always a dominant population compared to another Anopheles species. Because of the breeding ponds and the resting places were around the village, it is suspected that they mainly bit humans. The result of the observation in laboratory showed the life cycle of Anopheles barbirostris are around 20-27 days, and the longevity of 20 days. Morphological identification of Anopheles barbirostris by pictorial key for female Anopheles showed that there is no any significant difference. This research showed that Anopheles barbirostris was suspected as vector of malaria in Cineam village, Tasikmalaya.
In Poland in 2009 were reported 22 malaria cases confirmed according to the EU case definition for the purposes of routine surveillance system. All of them were imported, including 1 case of recrudescence, 86% from Africa. In 18 cases P falciparum etiology was confirmed and in 2--P vivax, in 1--P ovale and 1 P malariae. Most cases occurred in the age group 21-40 years, there were 21 cases in males and 1 in female. Common reasons for travel to endemic countries were work-related visits (14 cases) and tourism (6 cases), one person who visited the family and in one case unknown reason for travel. Three persons used chemoprophylaxis during their travel but only one of them appropriately, relevant information was missing in 5 cases. Clinical course was severe in 7 cases of P falciparum malaria and medium-severe in one case. In 2009, there were no malaria deaths in Poland. Education on the prevention of malaria and pretravel health advising is still greatly needed.
Stephen J Rogerson
Full Text Available Pregnant women are especially susceptible to malaria infection. Without existing immunity, severe malaria can develop requiring emergency treatment, and pregnancy loss is common. In semi-immune women, consequences of malaria for the mother include anaemia while stillbirth, premature delivery and foetal growth restriction affect the developing foetus. Preventive measures include insecticide-treated nets and (in some African settings intermittent preventive treatment. Prompt management of maternal infection is key, using parenteral artemisinins for severe malaria, and artemisinin combination treatments (ACTs in the second and third trimesters of pregnancy. ACTs may soon also be recommended as an alternative to quinine as a treatment in the first trimester of pregnancy. Monitoring the safety of antimalarials and understanding their pharmacokinetics is particularly important in pregnancy with the altered maternal physiology and the risks to the developing foetus. As increasing numbers of countries embrace malaria elimination as a goal, the special needs of the vulnerable group of pregnant women and their infants should not be overlooked.
Banchongaksorn, T; Prajakwong, S; Rooney, W; Vickers, P
The rapid manual ParaSight-F test of Plasmodium falciparum malaria, an antigen capture test for detecting trophozoite-derived histidine rich protein-2 (PF HRP-2), is simple to perform and provides a definite diagnosis within 10 minutes. During an operational trial at health centers and mobile malaria units where microscopical diagnosis is not available and using defined symptom screening criteria, 3,361 subjects were tested yielding 618 positives (18.4%) for PF-HRP-2 by ParaSight-F. Microscopic examination of the same subjects by thick blood film examined 7 days later at a malaria clinic showed 578 falciparum, and 349 vivax and mixed infection (F+V) 41. The technology proved highly effective in detecting falciparum malaria at the peripheral levels where access to malaria laboratory services are difficult, thus allowing immediate administration of a complete course of treatment in the absence of a microscopic examination.
Full Text Available Abstract Background Severe and cerebral malaria are associated with endothelial activation. Angiopoietin-1 (ANG-1 and angiopoietin-2 (ANG-2 are major regulators of endothelial activation and integrity. The aim of this study was to investigate the clinical utility of whole blood angiopoietin (ANG levels as biomarkers of disease severity in Plasmodium falciparum malaria. Methods The utility of whole blood ANG levels was examined in Thai patients to distinguish cerebral (CM; n = 87 and severe (non-cerebral malaria (SM; n = 36 from uncomplicated malaria (UM; n = 70. Comparative statistics are reported using a non-parametric univariate analysis (Kruskal-Wallis test or Chi-squared test, as appropriate. Multivariate binary logistic regression was used to examine differences in whole blood protein levels between groups (UM, SM, CM, adjusting for differences due to ethnicity, age, parasitaemia and sex. Receiver operating characteristic curve analysis was used to assess the diagnostic accuracy of the ANGs in their ability to distinguish between UM, SM and CM. Cumulative organ injury scores were obtained for patients with severe disease based on the presence of acute renal failure, jaundice, severe anaemia, circulatory collapse or coma. Results ANG-1 and ANG-2 were readily detectable in whole blood. Compared to UM there were significant decreases in ANG-1 (p Conclusions These results suggest that whole blood ANG-1/2 levels are promising clinically informative biomarkers of disease severity in malarial syndromes.
Izak, Dariusz; Klim, Joanna; Kaczanowski, Szymon
Malaria remains one of the highest mortality infectious diseases. Malaria is caused by parasites from the genus Plasmodium. Most deaths are caused by infections involving Plasmodium falciparum, which has a complex life cycle. Malaria parasites are extremely well adapted for interactions with their host and their host's immune system and are able to suppress the human immune system, erase immunological memory and rapidly alter exposed antigens. Owing to this rapid evolution, parasites develop drug resistance and express novel forms of antigenic proteins that are not recognized by the host immune system. There is an emerging need for novel interventions, including novel drugs and vaccines. Designing novel therapies requires knowledge about host-parasite interactions, which is still limited. However, significant progress has recently been achieved in this field through the application of bioinformatics analysis of parasite genome sequences. In this review, we describe the main achievements in 'malarial' bioinformatics and provide examples of successful applications of protein sequence analysis. These examples include the prediction of protein functions based on homology and the prediction of protein surface localization via domain and motif analysis. Additionally, we describe PlasmoDB, a database that stores accumulated experimental data. This tool allows data mining of the stored information and will play an important role in the development of malaria science. Finally, we illustrate the application of bioinformatics in the development of population genetics research on malaria parasites, an approach referred to as reverse ecology.
Neafsey, Daniel E; Juraska, Michal; Bedford, Trevor
Background The RTS,S/AS01 vaccine targets the circumsporozoite protein of Plasmodium falciparum and has partial protective efficacy against clinical and severe malaria disease in infants and children. We investigated whether the vaccine efficacy was specific to certain parasite genotypes at the c......Background The RTS,S/AS01 vaccine targets the circumsporozoite protein of Plasmodium falciparum and has partial protective efficacy against clinical and severe malaria disease in infants and children. We investigated whether the vaccine efficacy was specific to certain parasite genotypes...... protein had on vaccine efficacy against first episodes of clinical malaria within 1 year after vaccination. Results In the per-protocol group of 4577 RTS,S/AS01-vaccinated participants and 2335 control-vaccinated participants who were 5 to 17 months of age, the 1-year cumulative vaccine efficacy was 50.......3% (95% confidence interval [CI], 34.6 to 62.3) against clinical malaria in which parasites matched the vaccine in the entire circumsporozoite protein C-terminal (139 infections), as compared with 33.4% (95% CI, 29.3 to 37.2) against mismatched malaria (1951 infections) (P=0.04 for differential vaccine...
Rojo-Marcos, Gerardo; Cuadros-González, Juan
Malaria is life threatening and requires urgent diagnosis and treatment. Incidence and mortality are being reduced in endemic areas. Clinical features are unspecific so in imported cases it is vital the history of staying in a malarious area. The first line treatments for Plasmodium falciparum are artemisinin combination therapies, chloroquine in most non-falciparum and intravenous artesunate if any severity criteria. Human infections with intestinal protozoa are distributed worldwide with a high global morbid-mortality. They cause diarrhea and sometimes invasive disease, although most are asymptomatic. In our environment populations at higher risk are children, including adopted abroad, immune-suppressed, travelers, immigrants, people in contact with animals or who engage in oral-anal sex. Diagnostic microscopic examination has low sensitivity improving with antigen detection or molecular methods. Antiparasitic resistances are emerging lately. Copyright © 2016 Elsevier España, S.L.U. y Sociedad Española de Enfermedades Infecciosas y Microbiología Clínica. All rights reserved.
Lennartz, Frank; Adams, Yvonne; Bengtsson, Anja
Cerebral malaria is a deadly outcome of infection by Plasmodium falciparum, occurring when parasite-infected erythrocytes accumulate in the brain. These erythrocytes display parasite proteins of the PfEMP1 family that bind various endothelial receptors. Despite the importance of cerebral malaria...
Mace, Kimberly E; Arguin, Paul M
Malaria in humans is caused by intraerythrocytic protozoa of the genus Plasmodium. These parasites are transmitted by the bite of an infective female Anopheles mosquito. The majority of malaria infections in the United States occur among persons who have traveled to regions with ongoing malaria transmission. However, malaria is occasionally acquired by persons who have not traveled out of the country through exposure to infected blood products, congenital transmission, laboratory exposure, or local mosquitoborne transmission. Malaria surveillance in the United States is conducted to identify episodes of local transmission and to guide prevention recommendations for travelers. This report summarizes cases in persons with onset of illness in 2014 and trends during previous years. Malaria cases diagnosed by blood film, polymerase chain reaction, or rapid diagnostic tests are reported to local and state health departments by health care providers or laboratory staff. Case investigations are conducted by local and state health departments, and reports are transmitted to CDC through the National Malaria Surveillance System, National Notifiable Diseases Surveillance System, or direct CDC consultations. CDC conducts antimalarial drug resistance marker testing on blood samples submitted by health care providers or local or state health departments. Data from these reporting systems serve as the basis for this report. CDC received reports of 1,724 confirmed malaria cases, including one congenital case and two cryptic cases, with onset of symptoms in 2014 among persons in the United States. The number of confirmed cases in 2014 is consistent with the number of confirmed cases reported in 2013 (n = 1,741; this number has been updated from a previous publication to account for delayed reporting for persons with symptom onset occurring in late 2013). Plasmodium falciparum, P. vivax, P. ovale, and P. malariae were identified in 66.1%, 13.3%, 5.2%, and 2.7% of cases, respectively
C. T. Daniel-Ribeiro
Full Text Available The present paper reviews our recent data concerning the use of immunological methods employing monoclonal antibodies and synthetic peptides to study malaria transmission and immunity and to diagnose plasmodial infection. As concerns malaria transmission, we studied the main vectors of human malaria and the plasmodial species transmitted in endemic areas of Rondônia state, Brazil. The natural infection on anopheline was evaluated by immunoradiometric assay (IRMA using monoclonal antibodies to an immunodominant sporozoite surface antigen (CS protein demonstrated to be species specific. Our results showed that among six species of Anopheles found infected, An. darlingi was the main vector transmitting Plasmodium falciparum and P. vivax malaria in the immediate vicinity of houses. In order to assess the level of anti-CS antibodies we studied, by IRMA using the synthetic peptide corresponding to the repetitive epitope of the sporozoite CS protein, sera of individuals living in the same areas where the entomological survey has been performed. In this assay the prevalence of anti-CS antibodies was very low and did not reflect the malaria transmission rate in the studied areas. In relation to malaria diagnosis, a monoclonal antibody specific to an epitope of a 50 kDa exoantigen, the major component of supernatant collected at the time of schizont rupture, was used as a probe for the detection of P. falciparum antigens. This assay seemed to be more sensitive than parasitological examination for malaria diagnosis since it was able to detect plasmodial antigens in both symptomatic and asymtomatic individuals with negative thick blood smear at different intervals after a last parasitologically confirmed confirmed attack of malaria.
Enweronu-Laryea Christabel C
Full Text Available Abstract Background Congenital malaria is defined as malaria parasitaemia in the first week of life. The reported prevalence of congenital malaria in sub-Saharan Africa is variable (0 - 46%. Even though the clinical significance of congenital malaria parasitaemia is uncertain, anti-malarial drugs are empirically prescribed for sick newborns by frontline health care workers. Data on prevalence of congenital malaria in high-risk newborns will inform appropriate drug use and timely referral of sick newborns. Methods Blood samples of untreated newborns less than 1 week of age at the time of referral to Korle Bu Teaching hospital in Accra, Ghana during the peak malaria seasons (April to July of 2008 and 2010 were examined for malaria parasites by, i Giemsa-stained thick and thin blood smears for parasite count and species identification, ii histidine-rich protein- and lactic dehydrogenase-based rapid diagnosis tests, or iii polymerase chain reaction amplification of the merozoite surface protein 2 gene, for identification of sub-microscopic parasitaemia. Other investigations were also done as clinically indicated. Results In 2008, nine cases of Plasmodium falciparum parasitaemia were diagnosed by microscopy in 405 (2.2% newborns. All the nine newborns had low parasite densities (≤50 per microlitre. In 2010, there was no case of parasitaemia by either microscopy or rapid diagnosis tests in 522 newborns; however, 56/467 (12% cases of P. falciparum were detected by polymerase chain reaction. Conclusion Congenital malaria is an uncommon cause of clinical illness in high-risk untreated newborns referred to a tertiary hospital in the first week of life. Empirical anti-malarial drug treatment for sick newborns without laboratory confirmation of parasitaemia is imprudent. Early referral of sick newborns to hospitals with resources and skills for appropriate care is recommended.
Full Text Available Malaria prevention and iron supplementation are associated with improved maternal and infant outcomes. However, evidence from studies in children suggests iron may adversely modify the risk of malaria. We reviewed the evidence in pregnancy of the association between malaria and markers of iron status, iron supplementation or parenteral treatment.We searched MEDLINE, EMBASE, the Cochrane Central Register of Controlled Trials, the Global Health Library, and the Malaria in Pregnancy library to identify studies that investigated the association between iron status, iron treatment or supplementation during pregnancy and malaria. Thirty one studies contributed to the analysis; 3 experimental and 28 observational studies. Iron supplementation was not associated with an increased risk of P. falciparum malaria during pregnancy or delivery in Africa (summary Relative Risk = 0.89, 95% Confidence Interval (CI 0.66-1.20, I(2 = 78.8%, 5 studies. One study in Asia reported an increased risk of P. vivax within 30 days of iron supplementation (e.g. adjusted Hazard Ratio = 1.75, 95% CI 1.14-2.70 for 1-15 days, but not after 60 days. Iron deficiency (based on ferritin and C-reactive protein was associated with lower odds for malaria infection (summary Odds Ratio = 0.35, 0.24-0.51, I(2 = 59.2%, 5 studies. With the exception of the acute phase protein ferritin, biomarkers of iron deficiency were generally not associated with malaria infection.Iron supplementation was associated with a temporal increase in P vivax, but not with an increased risk of P. falciparum; however, data are insufficient to rule out the potential for an increased risk of P. falciparum. Iron deficiency was associated with a decreased malaria risk in pregnancy only when measured with ferritin. Until there is more evidence, it is prudent to provide iron in combination with malaria prevention during pregnancy.
Abkallo, Hussein M.
Identifying the genetic determinants of phenotypes that impact disease severity is of fundamental importance for the design of new interventions against malaria. Here we present a rapid genome-wide approach capable of identifying multiple genetic drivers of medically relevant phenotypes within malaria parasites via a single experiment at single gene or allele resolution. In a proof of principle study, we found that a previously undescribed single nucleotide polymorphism in the binding domain of the erythrocyte binding like protein (EBL) conferred a dramatic change in red blood cell invasion in mutant rodent malaria parasites Plasmodium yoelii. In the same experiment, we implicated merozoite surface protein 1 (MSP1) and other polymorphic proteins, as the major targets of strain-specific immunity. Using allelic replacement, we provide functional validation of the substitution in the EBL gene controlling the growth rate in the blood stages of the parasites.
Bynum, W F
British India was an important site of much important malaria research. Although Ronald Ross left India in 1899, a number of malariologists continued the task of evaluating the incidence and distribution of malaria in the country. Implementing practical solutions was hampered by formidable social and economic problems. This paper examines the Indian situation in the late 1920s, through a retrospective selection of writings chosen by J.A. Sinton for reproduction in an early issue of 'The records of the malaria survey of India', and the analysis of the Indian malaria situation through a visit of the League of Nations Malaria Commission in 1929.
Arcelia, F.; Asymida, F.; Lubis, N. F. M.; Pasaribu, A. P.
Plasmodium parasites caused Malaria. Indonesia is one of the countries in Southeast Asia that endemic to malaria. The burden of malaria is more in the eastern part of Indonesia than the Western part as well as the endemicity. Some cases of malaria will develop to severe form. Usually, the manifestation of children and adult are different. We reported a severe case of malaria in a 14-year-old boy who develops several manifestations such as anemia, hypoglycemia, sepsis and black water fever. We successfully treated the patient with Artesunate intravenous and continued with Dihydroartemisinin-piperaquine.
Jignesh B Vaishnani
Full Text Available Malaria is an infectious disease caused by protozoa of the genus Plasmodium. Cutaneous lesions in malaria are rarely reported and include urticaria, angioedema, petechiae, purpura, and disseminated intravascular coagulation (DIC. Here, five malaria cases associated with cutaneous lesions have been described. Out of the five cases of malaria, two were associated with urticaria and angioedema, one case was associated with urticaria, and other two were associated with reticulated blotchy erythema with petechiae. Most of the cutaneous lesions in malaria were nonspecific and reflected the different immunopathological mechanism in malarial infection.
Adu, Bright; Cherif, Mariama K; Bosomprah, Samuel
therefore need to be evaluated against different malaria endemicity backgrounds. METHODS: The associations between antibody responses to the chimeric merozoite surface protein 1 block 2 hybrid (MSP1 hybrid), glutamate-rich protein region 2 (GLURP R2) and the peptide AS202.11, and the risk of malaria were...
Smith, Joseph D; Rowe, J Alexandra; Higgins, Matthew K
Cytoadhesion of Plasmodium falciparum-infected erythrocytes to host microvasculature is a key virulence determinant. Parasite binding is mediated by a large family of clonally variant adhesion proteins, termed P. falciparum erythrocyte membrane protein 1 (PfEMP1), encoded by var genes and expressed...
Recht, Judith; Siqueira, André M; Monteiro, Wuelton M; Herrera, Sonia M; Herrera, Sócrates; Lacerda, Marcus V G
In spite of significant progress towards malaria control and elimination achieved in South America in the 2000s, this mosquito-transmitted tropical disease remains an important public health concern in the region. Most malaria cases in South America come from Amazon rain forest areas in northern countries, where more than half of malaria is caused by Plasmodium vivax, while Plasmodium falciparum malaria incidence has decreased in recent years. This review discusses current malaria data, policies and challenges in four South American Amazon countries: Brazil, Colombia, Peru and the Bolivarian Republic of Venezuela. Challenges to continuing efforts to further decrease malaria incidence in this region include: a significant increase in malaria cases in recent years in Venezuela, evidence of submicroscopic and asymptomatic infections, peri-urban malaria, gold mining-related malaria, malaria in pregnancy, glucose-6-phosphate dehydrogenase (G6PD) deficiency and primaquine use, and possible under-detection of Plasmodium malariae. Some of these challenges underscore the need to implement appropriate tools and procedures in specific regions, such as a field-compatible molecular malaria test, a P. malariae-specific test, malaria diagnosis and appropriate treatment as part of regular antenatal care visits, G6PD test before primaquine administration for P. vivax cases (with weekly primaquine regimen for G6PD deficient individuals), single low dose of primaquine for P. falciparum malaria in Colombia, and national and regional efforts to contain malaria spread in Venezuela urgently needed especially in mining areas. Joint efforts and commitment towards malaria control and elimination should be strategized based on examples of successful regional malaria fighting initiatives, such as PAMAFRO and RAVREDA/AMI.
Hansen, K. S.; Lesner, T. H.; Østerdal, L. P.
Background: Malaria continues to be a serious public health problem particularly in Africa. Many people infected with malaria do not access effective treatment due to high price. At the same time many individuals receiving malaria drugs do not suffer from malaria because of the common practice of...... seeking care for malaria in the private sector. © 2016 The Author(s)....
Årdal, Christine; Røttingen, John-Arne
Greater investment is required in developing new drugs and vaccines against malaria in order to eradicate malaria. These precious funds must be carefully managed to achieve the greatest impact. We evaluate existing efforts to discover and develop new drugs and vaccines for malaria to determine how best malaria R&D can benefit from an enhanced open source approach and how such a business model may operate. We assess research articles, patents, clinical trials and conducted a smaller survey among malaria researchers. Our results demonstrate that the public and philanthropic sectors are financing and performing the majority of malaria drug/vaccine discovery and development, but are then restricting access through patents, 'closed' publications and hidden away physical specimens. This makes little sense since it is also the public and philanthropic sector that purchases the drugs and vaccines. We recommend that a more "open source" approach is taken by making the entire value chain more efficient through greater transparency which may lead to more extensive collaborations. This can, for example, be achieved by empowering an existing organization like the Medicines for Malaria Venture (MMV) to act as a clearing house for malaria-related data. The malaria researchers that we surveyed indicated that they would utilize such registry data to increase collaboration. Finally, we question the utility of publicly or philanthropically funded patents for malaria medicines, where little to no profits are available. Malaria R&D benefits from a publicly and philanthropically funded architecture, which starts with academic research institutions, product development partnerships, commercialization assistance through UNITAID and finally procurement through mechanisms like The Global Fund to Fight AIDS, Tuberculosis and Malaria and the U.S.' President's Malaria Initiative. We believe that a fresh look should be taken at the cost/benefit of patents particularly related to new malaria
Kondrashin, Anatoly V; Sharipov, Azizullo S; Kadamov, Dilshod S; Karimov, Saifuddin S; Gasimov, Elkhan; Baranova, Alla M; Morozova, Lola F; Stepanova, Ekaterina V; Turbabina, Natalia A; Maksimova, Maria S; Morozov, Evgeny N
Malaria was eliminated in Tajikistan by the beginning of the 1960s. However, sporadic introduced cases of malaria occurred subsequently probably as a result of transmission from infected mosquito Anopheles flying over river the Punj from the border areas of Afghanistan. During the 1970s and 1980s local outbreaks of malaria were reported in the southern districts bordering Afghanistan. The malaria situation dramatically changed during the 1990s following armed conflict and civil unrest in the newly independent Tajikistan, which paralyzed health services including the malaria control activities and a large-scale malaria epidemic occurred with more than 400,000 malaria cases. The malaria epidemic was contained by 1999 as a result of considerable financial input from the Government and the international community. Although Plasmodium falciparum constituted only about 5% of total malaria cases, reduction of its incidence was slower than that of Plasmodium vivax. To prevent increase in P. falciparum malaria both in terms of incidence and territory, a P. falciparum elimination programme in the Republic was launched in 200, jointly supported by the Government and the Global Fund for control of AIDS, tuberculosis and malaria. The main activities included the use of pyrethroids for the IRS with determined periodicity, deployment of mosquito nets, impregnated with insecticides, use of larvivorous fishes as a biological larvicide, implementation of small-scale environmental management, and use of personal protection methods by population under malaria risk. The malaria surveillance system was strengthened by the use of ACD, PCD, RCD and selective use of mass blood surveys. All detected cases were timely epidemiologically investigated and treated based on the results of laboratory diagnosis. As a result, by 2009, P. falciparum malaria was eliminated from all of Tajikistan, one year ahead of the originally targeted date. Elimination of P. falciparum also contributed towards
Full Text Available Greater investment is required in developing new drugs and vaccines against malaria in order to eradicate malaria. These precious funds must be carefully managed to achieve the greatest impact. We evaluate existing efforts to discover and develop new drugs and vaccines for malaria to determine how best malaria R&D can benefit from an enhanced open source approach and how such a business model may operate. We assess research articles, patents, clinical trials and conducted a smaller survey among malaria researchers. Our results demonstrate that the public and philanthropic sectors are financing and performing the majority of malaria drug/vaccine discovery and development, but are then restricting access through patents, 'closed' publications and hidden away physical specimens. This makes little sense since it is also the public and philanthropic sector that purchases the drugs and vaccines. We recommend that a more "open source" approach is taken by making the entire value chain more efficient through greater transparency which may lead to more extensive collaborations. This can, for example, be achieved by empowering an existing organization like the Medicines for Malaria Venture (MMV to act as a clearing house for malaria-related data. The malaria researchers that we surveyed indicated that they would utilize such registry data to increase collaboration. Finally, we question the utility of publicly or philanthropically funded patents for malaria medicines, where little to no profits are available. Malaria R&D benefits from a publicly and philanthropically funded architecture, which starts with academic research institutions, product development partnerships, commercialization assistance through UNITAID and finally procurement through mechanisms like The Global Fund to Fight AIDS, Tuberculosis and Malaria and the U.S.' President's Malaria Initiative. We believe that a fresh look should be taken at the cost/benefit of patents particularly related
Bhatia, Rajesh; Rastogi, Rakesh Mani; Ortega, Leonard
Asia ranks second to Africa in terms of malaria burden. In 19 countries of Asia, malaria is endemic and 2.31 billion people or 62% of the total population in these countries are at risk of malaria. In 2010, WHO estimated around 34.8 million cases and 45,600 deaths due to malaria in Asia. In 2011, 2.7 million cases and > 2000 deaths were reported. India, Indonesia, Myanmar and Pakistan are responsible for >85% of the reported cases (confirmed) and deaths in Asia. In last 10 yr, due to availability of donor's fund specially from Global fund, significant progress has been made by the countries in Asia in scaling-up malaria control interventions which were instrumental in reducing malaria morbidity and mortality significantly. There is a large heterogeneity in malaria epidemiology in Asia. As a result, the success in malaria control/elimination is also diverse. As compared to the data of the year 2000, out of 19 malaria endemic countries, 12 countries were able to reduce malaria incidence (microscopically confirmed cases only) by 75%. Two countries, namely Bangladesh and Malaysia are projected to reach 75% reduction by 2015 while India is projected to reach 50-75% only by 2015. The trend could not be assessed in four countries, namely Indonesia, Myanmar, Pakistan and Timor-Leste due to insufficient consistent data. Numerous key challenges need to be addressed to sustain the gains and eliminate malaria in most parts of Asia. Some of these are to control the spread of resistance in Plasmodium falciparum to artemisinin, control of outdoor transmission, control of vivax malaria and ensuring universal coverage of key interventions. Asia has the potential to influence the malaria epidemiology all over the world as well as to support the global efforts in controlling and eliminating malaria through production of quality-assured ACTs, RDTs and long-lasting insecticidal nets.
Croft, Ashley M
Malaria transmission occurs most frequently in environments with humidity greater than 60% and ambient temperature of 25 °C to 30 °C. Risks increase with longer visits and depend on activity. Infection can follow a single mosquito bite. Incubation is usually 10 to 14 days but can be up to 18 months depending on the strain of parasite. We conducted a systematic review and aimed to answer the following clinical questions: What are the effects of non-drug preventive interventions in non-pregnant adult travellers? What are the effects of drug prophylaxis in non-pregnant adult travellers? What are the effects of antimalaria vaccines in adult and child travellers? What are the effects of antimalaria interventions in child travellers, pregnant travellers, and in airline pilots? We searched: Medline, Embase, The Cochrane Library, and other important databases up to November 2009 (Clinical Evidence reviews are updated periodically, please check our website for the most up-to-date version of this review). We included harms alerts from relevant organisations such as the US Food and Drug Administration (FDA) and the UK Medicines and Healthcare products Regulatory Agency (MHRA). We found 79 systematic reviews, RCTs, or observational studies that met our inclusion criteria. We performed a GRADE evaluation of the quality of evidence for interventions. In this systematic review we present information relating to the effectiveness and safety of the following interventions: aerosol insecticides, amodiaquine, air conditioning and electric fans, atovaquone-proguanil, biological control measures, chloroquine (alone or with proguanil), diethyltoluamide (DEET), dietary supplementation, doxycycline, electronic mosquito repellents, full-length and light-coloured clothing, insecticide-treated clothing/nets, mefloquine, mosquito coils and vapourising mats, primaquine, pyrimethamine-dapsone, pyrimethamine-sulfadoxine, smoke, topical (skin-applied) insect repellents, and vaccines.
Essuman, Vera A; Ntim-Amponsah, Christine T; Astrup, Birgitte S
diagnostic tool. This study was designed to determine the diagnostic usefulness of retinopathy on ophthalmoscopy in severe malaria syndromes: Cerebral malaria (CM) and non-cerebral severe malaria (non-CM), i.e. malaria with respiratory distress (RD) and malaria with severe anaemia (SA), in Ghanaian children...
Yaw A Afrane
Full Text Available Currently, intensive malaria control programs are being implemented in Africa to reduce the malaria burden. Clinical malaria data from hospitals are valuable for monitoring trends in malaria morbidity and for evaluating the impacts of these interventions. However, the reliability of hospital-based data for true malaria incidence is often questioned because of diagnosis accuracy issues and variation in access to healthcare facilities among sub-groups of the population. This study investigated how diagnosis and treatment practices of malaria cases in hospitals affect reliability of hospital malaria data.The study was undertaken in health facilities in western Kenya. A total of 3,569 blood smears were analyzed after being collected from patients who were requested by clinicians to go to the hospital's laboratory for malaria testing. We applied several quality control measures for clinical malaria diagnosis. We compared our slide reading results with those from the hospital technicians. Among the 3,390 patients whose diagnoses were analyzed, only 36% had clinical malaria defined as presence of any level of parasitaemia and fever. Sensitivity and specificity of clinicians' diagnoses were 60.1% (95% CI: 61.1-67.5 and 75.0% (95% CI: 30.8-35.7, respectively. Among the 980 patients presumptively treated with an anti-malarial by the clinicians without laboratory diagnosis, only 47% had clinical malaria.These findings revealed substantial over-prescription of anti-malarials and misdiagnosis of clinical malaria. More than half of the febrile cases were not truly clinical malaria, but were wrongly diagnosed and treated as such. Deficiency in malaria diagnosis makes health facility data unreliable for monitoring trends in malaria morbidity and for evaluating impacts of malaria interventions. Improving malaria diagnosis should be a top priority in rural African health centers.
Sørensen, P G; Mickley, H; Schmidt, K G
On return from Liberia, a previously healthy 36-year-old man showed signs of malaria accompanied by severe haemolysis and slight thrombocytopenia. We found evidence of a platelet-associated IgG being responsible for the thrombocytopenia, inasmuch as the direct platelet suspension immunofluorescen...
In Poland in 2007 there were 11 malaria cases confirmed according to the European Union cases definition reported through the routine surveillance system. All of them were imported, 82% from Africa, including 2 cases of relapse. Invasion with Plasmodium falciparum was diagnosed in 7 cases, mixed invasion in 2 cases and P. vivax- in one case. The majority of cases were in the age group 35-45 (8 cases) and were males (10 cases). Common reasons for travel to endemic countries were work-related (5 cases) and tourism or family visits (4 cases). Approximately half of the cases for whom the information was available used malaria chemoprophylaxis during their travel. Clinical course was severe in one case of P. falciparum malaria and the person died of the disease. The decreasing trend in malaria incidence in Poland is likely related to incomplete reporting as tourist and professional travel to endemic areas has not decreased and there is no indication of wider use ofchemoprophylaxis.
Full Text Available Objective: To assess effect of nicotine, major addictive component of tobacco smoke, on outcomes of the deadly malaria parasite using mice as animal model. Methods: Male Swiss albino mice were treated with 100 and 200 µg/mL of nicotine in drinking water daily for 6 weeks followed by Plasmodium berghei ANKA (PbA infection. On the seventh day of post infection (p.i., physical, clinical, histopathological, biochemical and hematological parameters were assessed. Data were analyzed using SPSS software. Results: Nicotine was significantly (P < 0.05 positively associated with lower levels of hemoglobin (Hb, hematocrit (HCT, red blood cells (RBCs, C-reactive protein (CRP and uric acid (UA, higher risk to incidence of pulmonary edema, elevated level of liver and kidney biomarkers. Also significant increment (P < 0.01 of monocyte-lymphocyte count ratio (MLCR was observed. Risk to high temperature, lower platelet count, high parastemia and cerebral malaria was lesser in mice treated with nicotine (100 and 200 µg/mL followed by PbA infection than the positive control. Lack of neurological symptoms might be accounted to the anti-inflammatory property of nicotine that could inhibit production of pro-inflammatory mediators responsible for occurrence of cerebral malaria. Conclusions: This study showed that despite down regulation of most cerebral malaria symptoms nicotine was strongly associated with increased risk to most clinical symptoms of malaria. Thus, like in respiratory infections, nicotine use might enhance susceptibility to malaria.
Marrelli, Mauro Toledo; Brotto, Marco
Malaria remains one of the most important infectious diseases in the world, being a significant public health problem associated with poverty and it is one of the main obstacles to the economy of an endemic country. Among the several complications, the effects of malaria seem to target the skeletal muscle system, leading to symptoms, such as muscle aches, muscle contractures, muscle fatigue, muscle pain, and muscle weakness. Malaria cause also parasitic coronary artery occlusion. This article reviews the current knowledge regarding the effect of malaria disease and the anti-malarial drugs on skeletal and cardiac muscles. Research articles and case report publications that addressed aspects that are important for understanding the involvement of malaria parasites and anti-malarial therapies affecting skeletal and cardiac muscles were analysed and their findings summarized. Sequestration of red blood cells, increased levels of serum creatine kinase and reduced muscle content of essential contractile proteins are some of the potential biomarkers of the damage levels of skeletal and cardiac muscles. These biomarkers might be useful for prevention of complications and determining the effectiveness of interventions designed to protect cardiac and skeletal muscles from malaria-induced damage.
Ferreira, Marcelo U; Castro, Marcia C
Brazil currently contributes 42 % of all malaria cases reported in the Latin America and the Caribbean, a region where major progress towards malaria elimination has been achieved in recent years. In 2014, malaria burden in Brazil (143,910 microscopically confirmed cases and 41 malaria-related deaths) has reached its lowest levels in 35 years, Plasmodium falciparum is highly focal, and the geographic boundary of transmission has considerably shrunk. Transmission in Brazil remains entrenched in the Amazon Basin, which accounts for 99.5 % of the country's malaria burden. This paper reviews major lessons learned from past and current malaria control policies in Brazil. A comprehensive discussion of the scientific and logistic challenges that may impact malaria elimination efforts in the country is presented in light of the launching of the Plan for Elimination of Malaria in Brazil in November 2015. Challenges for malaria elimination addressed include the high prevalence of symptomless and submicroscopic infections, emerging anti-malarial drug resistance in P. falciparum and Plasmodium vivax and the lack of safe anti-relapse drugs, the largely neglected burden of malaria in pregnancy, the need for better vector control strategies where Anopheles mosquitoes present a highly variable biting behaviour, human movement, the need for effective surveillance and tools to identify foci of infection in areas with low transmission, and the effects of environmental changes and climatic variability in transmission. Control actions launched in Brazil and results to come are likely to influence control programs in other countries in the Americas.
of malaria among pregnant women in riverine community in Bayelsa State, ... at high risk of the effects of malaria infection and need special protective .... mentioned maintenance of clean environment, as other methods of preventing malaria.
Abstract: Despite existence of effective tools for malaria control, malaria ... breaks from traditional approach that tend to study low uptake of health ... Key words: scepticism, low uptake, mosquito nets, malaria, social marketing, Tanzania.
Rulisa, S.; Mens, P.F.; Karema, C.; Schallig, H.D.F.H.; Kaligirwa, N.; Vyankandondera, J.; de Vries, P.J.
Background: Malaria has a negative effect on pregnancy outcome, causing low birth weight, premature birth and stillbirths, particularly in areas with high malaria transmission. In Rwanda, malaria transmission intensity ranges from high to nil, probably associated with variable altitudes. Overall,
AJRH Managing Editor
investigate factors that influence malaria prevention and control practices among pregnant ... treatment of clinical cases and the promotion of ... influence their decision regarding malaria ..... have the ability to purchase anti-malaria drugs that.
Brasil, Larissa W; Barbosa, Laila R A; de Araujo, Felipe J; da Costa, Allyson G; da Silva, Luan D O; Pinheiro, Suzana K; de Almeida, Anne C G; Kuhn, Andrea; Vitor-Silva, Sheila; de Melo, Gisely C; Monteiro, Wuelton M; de Lacerda, Marcus V G; Ramasawmy, Rajendranath
Toll-interacting protein is a negative regulator in the TLR signaling cascade, particularly by impeding the TLR2 and, TLR4 pathway. Recently, TOLLIP was shown to regulate human TLR signaling pathways. Two common TOLLIP polymorphisms (rs5743899 and rs3750920) were reported to be influencing IL-6, TNF and IL-10 expression. In this study, TOLLIP variants were investigated to their relation to Plasmodium vivax malaria in the Brazilian Amazon. This cohort study was performed in the municipalities of Careiro and, Manaus, in Western Brazilian Amazon. A total of 319 patients with P. vivax malaria and, 263 healthy controls with no previous history of malaria were included in the study. Genomic DNA was extracted from blood collected on filter paper, using the QIAamp ® DNA Mini Kit, according to the manufacturer's suggested protocol. The rs5743899 and rs3750920 polymorphisms of the TOLLIP gene were typed by PCR-RFLP. Homozygous individuals for the rs3750920 T allele gene had twice the risk of developing malaria when compared to individuals homozygous for the C allele (OR 2.0 [95% CI 1.23-3.07]; p = 0.004). In the dominant model, carriers the C allele indicates protection to malaria, carriers of the C allele were compared to individuals with the T allele, and the difference is highly significant (OR 0.52 [95% CI 0.37-0.76]; p = 0.0006). The linkage disequilibrium between the two polymorphisms was weak (r 2 = 0.037; D' = 0.27). These findings suggest that genes involved in the TLRs-pathway may be involved in malaria susceptibility. The association of the TOLLIP rs3750920 T allele with susceptibility to malaria further provides evidence that genetic variations in immune response genes may predispose individuals to malaria.
Full Text Available Malaria, caused by the apicomplexan parasite Plasmodium, still represents a major threat to human health and welfare and leads to about one million human deaths annually. Plasmodium is a rapidly multiplying unicellular organism undergoing a complex developmental cycle in man and mosquito - a life style that requires rapid adaptation to various environments. In order to deal with high fluxes of reactive oxygen species and maintain redox regulatory processes and pathogenicity, Plasmodium depends upon an adequate redox balance. By systematically studying the subcellular localization of the major antioxidant and redox regulatory proteins, we obtained the first complete map of redox compartmentation in Plasmodium falciparum. We demonstrate the targeting of two plasmodial peroxiredoxins and a putative glyoxalase system to the apicoplast, a non-photosynthetic plastid. We furthermore obtained a complete picture of the compartmentation of thioredoxin- and glutaredoxin-like proteins. Notably, for the two major antioxidant redox-enzymes--glutathione reductase and thioredoxin reductase--Plasmodium makes use of alternative-translation-initiation (ATI to achieve differential targeting. Dual localization of proteins effected by ATI is likely to occur also in other Apicomplexa and might open new avenues for therapeutic intervention.
Assan, Abraham; Takian, Amirhossein; Hanafi-Bojd, Ahmad Ali; Rahimiforoushani, Abbas; Nematolahi, Shahrzad
Despite continuing international attention to malaria prevention, the disease remains a global public health problem. We investigated socio-demographic factors influencing knowledge, attitudes, and practices about malaria in rural Ghana. Our survey looked at 354 households. Mean knowledge score was higher among individuals with a history of volunteers having visited their households to educate them about malaria; families with 4-6 members; and males. Households with at least one under-five-aged child also had significantly higher knowledge scores. Households with at least one pregnant woman evinced a positive attitude towards malaria prevention. National malaria control strategies have achieved positive results in the fight against malaria. Nonetheless, multipronged community-based health strategies that integrate malaria programs and population growth control initiatives may be able to reach by 2030 the sustainable development goal of eliminating malaria.
Kurtzhals, J A; Reimert, C M; Tette, E
To assess the eosinophil response to Plasmodium falciparum infection a cohort of initially parasite-free Ghanaian children was followed for 3 months. Seven of nine children who acquired an asymptomatic P. falciparum infection showed increase in eosinophil counts, while a decrease was found in seven...... of nine children with symptomatic malaria, and no change was observed in 14 children who remained parasite-free. In a hospital-based study, paediatric patients with cerebral malaria (CM), severe anaemia (SA), or uncomplicated malaria (UM) had uniformly low eosinophil counts during the acute illness...... followed by eosinophilia 30 days after cure. Plasma levels of eosinophil cationic protein (ECP) and eosinophil protein X (EPX) were measured as indicators of eosinophil activation. In spite of the low eosinophil counts, ECP levels were increased on day 0 and significantly higher in patients with CM...
Breeveld, Florence J. V.; Vreden, Stephen G. S.; Grobusch, Martin P.
Suriname has cleared malaria from its capital city and coastal areas mainly through the successful use of chloroquine and DDT (dichloro-diphenyl-trichloroethane) during the Global Malaria Eradication programme that started in 1955. Nonetheless, malaria transmission rates remained high in the
Dec 23, 2010 ... ... spraying techniques, Mexico has dramatically reduced malaria transmission. ... and the parasite, community perceptions of malaria, statistical analyses, and ... epidemiology, informatics, entomology, and the social sciences.
Houzé, Sandrine; Boutron, Isabelle; Marmorat, Anne; Dalichampt, Marie; Choquet, Christophe; Poilane, Isabelle; Godineau, Nadine; Le Guern, Anne-Sophie; Thellier, Marc; Broutier, Hélène; Fenneteau, Odile; Millet, Pascal; Dulucq, Stéphanie; Hubert, Véronique; Houzé, Pascal; Tubach, Florence; Le Bras, Jacques; Matheron, Sophie
We compared the performance of four rapid diagnostic tests (RDTs) for imported malaria, and particularly Plasmodium falciparum infection, using thick and thin blood smears as the gold standard. All the tests are designed to detect at least one protein specific to P. falciparum ( Plasmodium histidine-rich protein 2 (PfHRP2) or Plasmodium LDH (PfLDH)) and one pan-Plasmodium protein (aldolase or Plasmodium LDH (pLDH)). 1,311 consecutive patients presenting to 9 French hospitals with suspected malaria were included in this prospective study between April 2006 and September 2008. Blood smears revealed malaria parasites in 374 cases (29%). For the diagnosis of P. falciparum infection, the three tests detecting PfHRP2 showed high and similar sensitivity (96%), positive predictive value (PPV) (90%) and negative predictive value (NPV) (98%). The PfLDH test showed lower sensitivity (83%) and NPV (80%), despite good PPV (98%). For the diagnosis of non-falciparum species, the PPV and NPV of tests targeting pLDH or aldolase were 94–99% and 52–64%, respectively. PfHRP2-based RDTs are thus an acceptable alternative to routine microscopy for diagnosing P. falciparum malaria. However, as malaria may be misdiagnosed with RDTs, all negative results must be confirmed by the reference diagnostic method when clinical, biological or other factors are highly suggestive of malaria. PMID:24098699
Sharma Vinod P
Full Text Available Abstract Malaria is endemic in India with an estimated 70-100 million cases each year (1.6-1.8 million reported by NVBDCP; of this 50-55% are Plasmodium vivax and 45-50% Plasmodium falciparum. A recent study on malaria in pregnancy reported from undivided Madhya Pradesh state (includes Chhattisgarh state, that an estimated over 220,000 pregnant women contract malaria infection each year. Malaria in pregnancy caused- abortions 34.5%; stillbirths 9%; and maternal deaths 0.45%. Bulk of this tragic outcome can be averted by following the Roll Back Malaria/WHO recommendations of the use of malaria prevention i.e. indoor residual spraying (IRS/insecticide-treated bed nets (ITN preferably long-lasting treated bed nets (LLIN; intermittent preventive therapy (IPT; early diagnosis, prompt and complete treatment using microscopic/malaria rapid diagnostics test (RDT and case management. High incidence in pregnancy has arisen because of malaria surveillance lacking coverage, lack of age and sex wise data, staff shortages, and intermittent preventive treatment (IPT applicable in high transmission states/pockets is not included in the national drug policy- an essential component of fighting malaria in pregnancy in African settings. Inadequate surveillance and gross under-reporting has been highlighted time and again for over three decades. As a result the huge problem of malaria in pregnancy reported occasionally by researchers has remained hidden. Malaria in pregnancy may quicken severity in patients with drug resistant parasites, anaemia, endemic poverty, and malnutrition. There is, therefore, urgent need to streamline malaria control strategies to make a difference in tackling this grim scenario in human health.
Huang, Zhuojie; Tatem, Andrew J
Background Air travel has expanded at an unprecedented rate and continues to do so. Its effects have been seen on malaria in rates of imported cases, local outbreaks in non-endemic areas and the global spread of drug resistance. With elimination and global eradication back on the agenda, changing levels and compositions of imported malaria in malaria-free countries, and the threat of artemisinin resistance spreading from Southeast Asia, there is a need to better understand how the modern flow...
Rebekah van Bruggen
Full Text Available Pyruvate kinase (PKLR is a critical erythrocyte enzyme that is required for glycolysis and production of ATP. We have shown that Pklr deficiency in mice reduces the severity (reduced parasitemia, increased survival of blood stage malaria induced by infection with Plasmodium chabaudi AS. Likewise, studies in human erythrocytes infected ex vivo with P. falciparum show that presence of host PK-deficiency alleles reduces infection phenotypes. We have characterized the genetic diversity of the PKLR gene, including haplotype structure and presence of rare coding variants in two populations from malaria endemic areas of Thailand and Senegal. We investigated the effect of PKLR genotypes on rich longitudinal datasets including haematological and malaria-associated phenotypes. A coding and possibly damaging variant (R41Q was identified in the Thai population with a minor allele frequency of ~4.7%. Arginine 41 (R41 is highly conserved in the pyruvate kinase family and its substitution to Glutamine (R41Q affects protein stability. Heterozygosity for R41Q is shown to be associated with a significant reduction in the number of attacks with Plasmodium falciparum, while correlating with an increased number of Plasmodium vivax infections. These results strongly suggest that PKLR protein variants may affect the frequency, and the intensity of malaria episodes induced by different Plasmodium parasites in humans living in areas of endemic malaria.
Full Text Available Abstract Background Malaria is a significant threat to population health in the border areas of Yunnan Province, China. How to accurately measure malaria transmission is an important issue. This study aimed to examine the role of slide positivity rates (SPR in malaria transmission in Mengla County, Yunnan Province, China. Methods Data on annual malaria cases, SPR and socio-economic factors for the period of 1993 to 2008 were obtained from the Center for Disease Control and Prevention (CDC and the Bureau of Statistics, Mengla, China. Multiple linear regression models were conducted to evaluate the relationship between socio-ecologic factors and malaria incidence. Results The results show that SPR was significantly positively associated with the malaria incidence rates. The SPR (β = 1.244, p = 0.000 alone and combination (SPR, β = 1.326, p Conclusion SPR is a strong predictor of malaria transmission, and can be used to improve the planning and implementation of malaria elimination programmes in Mengla and other similar locations. SPR might also be a useful indicator of malaria early warning systems in China.
Hviid, L; Jakobsen, P H; Abu-Zeid, Y A
Malaria is caused by infection with protozoan parasites of the genus Plasmodium. It remains one of the most severe health problems in tropical regions of the world, and the rapid spread of resistance to drugs and insecticides has stimulated intensive research aimed at the development of a malaria...... vaccine. Despite this, no efficient operative vaccine is currently available. A large amount of information on T-cell responses to malaria antigens has been accumulated, concerning antigens derived from all stages of the parasite life cycle. The present review summarizes some of that information......, and discusses factors affecting the responses of T cells to malaria antigens....
Yamana, Teresa K.; Qiu, Xin; Eltahir, Elfatih A. B.
Malaria transmission is a complex system and in many parts of the world is closely related to climate conditions. However, studies on environmental determinants of malaria generally consider only concurrent climate conditions and ignore the historical or initial conditions of the system. Here, we demonstrate the concept of hysteresis in malaria transmission, defined as non-uniqueness of the relationship between malaria prevalence and concurrent climate conditions. We show the dependence of simulated malaria transmission on initial prevalence and the initial level of human immunity in the population. Using realistic time series of environmental variables, we quantify the effect of hysteresis in a modeled population. In a set of numerical experiments using HYDREMATS, a field-tested mechanistic model of malaria transmission, the simulated maximum malaria prevalence depends on both the initial prevalence and the initial level of human immunity in the population. We found the effects of initial conditions to be of comparable magnitude to the effects of interannual variability in environmental conditions in determining malaria prevalence. The memory associated with this hysteresis effect is longer in high transmission settings than in low transmission settings. Our results show that efforts to simulate and forecast malaria transmission must consider the exposure history of a location as well as the concurrent environmental drivers.
There were 22 malaria cases confirmed according to the European Union cases definition registered in Poland in 2008. All of them were imported, 13 cases (59%) from Africa, 3 from Asia, 5 from Oceania and 1 from South America. Invasion with Plasmodium falciparum was confirmed in 14 cases, P. vivax in 4 cases, mixed invasion in 2 cases and in 2 cases species of Plasmodium was undetermined. There were 13 cases in males and 9 in females. Age at onset ranged from 23 to 58 years and majority of cases were in the age group 25-40. Common reason for travel to endemic countries were tourism (11 cases) and work-related visits (7 cases). Clinical course was severe in 6 cases of P. falciparum malaria and 1 person died because of the disease. Nine cases used chemoprophylaxis during their travel but only one of them appropriately, relevant information was missing in 6 cases.
There were 19 cases of malaria meeting European Union case definition for confirmed case registered in Poland in 2006. All of them were imported, including 1 case of relapse: 17 from Africa, 1 from Asia and 1 from Oceania. Species of Plasmodium was determined for 12 cases (68%): P. falciparum in 12 cases and P. vivax in one. There were 15 cases in males and 4 in females. Age at onset ranged from 17 to 59 years and a considerable number of cases occurred in persons 50 years old or older (5.26%). Common reasons for travel to endemic countries included tourism or family visits (10 cases) and professional or missionary travel (5 cases). Only four cases used chemoprophylaxis and the relevant information was missing in 4 cases. In two cases of malaria caused by Pl. falciparum the clinical course was severe and one of them died.
Dembele, Bassidy; Yakubu, Abdul-Aziz
We extend the mathematical malaria epidemic model framework of Dembele et al. and use it to ``capture" the 2013 Centers for Disease Control and Prevention (CDC) reported data on the 2011 number of imported malaria cases in the USA. Furthermore, we use our ``fitted" malaria models for the top 20 countries of malaria acquisition by USA residents to study the impact of protecting USA residents from malaria infection when they travel to malaria endemic areas, the impact of protecting residents of malaria endemic regions from mosquito bites and the impact of killing mosquitoes in those endemic areas on the CDC number of imported malaria cases in USA. To significantly reduce the number of imported malaria cases in USA, for each top 20 country of malaria acquisition by USA travelers, we compute the optimal proportion of USA international travelers that must be protected against malaria infection and the optimal proportion of mosquitoes that must be killed.
Full Text Available Previous approaches in malaria treatment fail to reduce the morbidity and mortality of malaria. Widespread overuse of antimalarial treatment of clinical malaria may have contributed to increase drug resistance. Moreover, poor compliance or inadequate dosage also selects for parasite resistance. The paradigm of radical treatment using drug combinations may improve the cure rate and compliance, thereby preventing or delaying the emergence of parasites resistant to antimalarial drugs. The ideal combined antimalarial regimen in Indonesia should be safe and tolerated by all age groups, effective and rapidly acting for both P.falciparum and P.vivax malaria, short course, good compliance and acceptable, without resistance and/or cross-resistance or , not widely spread use, cost-effective and affordable. Artemisinin derivatives are the best partner drug for combination, with advantages that include: well absorbed, safe and well tolerated, rapidly converted to active metabolite, having very short half-life, broad specificity of action, and extremely potent. Current artemisinin-based combinations which are suitable for Indonesia include: amodiaquine plus artesunate given as single daily dose for 3 days (AQ3+ATS3, mefloquine plus artesunate given as single daily dose for 3 days (MQ3+ATS3, lumefantrine/benflumetol plus artemether given as twice daily dose for 3 days (COARTEMETHER, piperaquine plus dihydroartemisinin given as single daily dose for 2-3 days (PPQ2-3+DHA2-3, and piperaquine plus artemisinin given as single daily dose for 2 days (PPQ2+ATM2. Given the imbalance between rapid development of parasite resistance and slow availability of new effective antimalarial drugs, research and development of antimalarial drugs must be encouraged.
Full Text Available Malaria is the world's most prevalent infectious disease, a major cause of mortality, and a barrier to social and economic development and growth in many countries throughout the world. Antimalarials represent an important part of strategy to curbing this debilitating disease. The spread of drug resistance is becoming increasingly important. To date, parasite resistance to all but one case of antimalarials exists in most endemic countries. Meaning, new drug to combat the disease are a priority.
Full Text Available Transcription is a process by which the genetic information stored in DNA is converted into mRNA by enzymes known as RNA polymerase. Bacteria use only one RNA polymerase to transcribe all of its genes while eukaryotes contain three RNA polymerases to transcribe the variety of eukaryotic genes. RNA polymerase also requires other factors/proteins to produce the transcript. These factors generally termed as transcription factors (TFs are either associated directly with RNA polymerase or add in building the actual transcription apparatus. TFs are the most common tools that our cells use to control gene expression. Plasmodium falciparum is responsible for causing the most lethal form of malaria in humans. It shows most of its characteristics common to eukaryotic transcription but it is assumed that mechanisms of transcriptional control in P. falciparum somehow differ from those of other eukaryotes. In this article we describe the studies on the main TFs such as myb protein, high mobility group protein and ApiA2 family proteins from malaria parasite. These studies show that these TFs are slowly emerging to have defined roles in the regulation of gene expression in the parasite.
Ophorst, Olga J. A. E.; Radosevic, Katarina; Klap, Jaco M.; Sijtsma, Jeroen; Gillissen, Gert; Mintardjo, Ratna; van Ooij, Mark J. M.; Holterman, Lennart; Companjen, Arjen; Goudsmit, Jaap; Havenga, Menzo J. E.
Previously, we have shown the potency of recombinant Adenovirus serotype 35 viral vaccines (rAd35) to induce strong immune response against the circumsporozoite protein (CS) of the plasmodium parasite. To further optimize immunogenicity of Ad35-based malaria vaccines we formulated rAd35.CS vaccine
Dijk, M.R. van; Janse, C.J.; Thompson, J.; Waters, A.P.; Braks, J.A.M.; Dodemont, H.J.; Stunnenberg, H.G.; Gemert, G.J.A. van; Sauerwein, R.W.; Eling, W.M.C.
Fertilization and zygote development are obligate features of the malaria parasite life cycle and occur during parasite transmission to mosquitoes. The surface protein PFS48/45 is expressed by male and female gametes of Plasmodium falciparum and PFS48/45 antibodies prevent zygote development and
Hsieh, Fu-Lien; Turner, Louise; Bolla, Jani Reddy
CD36 is a scavenger receptor involved in fatty acid metabolism, innate immunity and angiogenesis. It interacts with lipoprotein particles and facilitates uptake of long chain fatty acids. It is also the most common target of the PfEMP1 proteins of the malaria parasite, Plasmodium falciparum...
de Langen, Adrianus J.; van Dillen, Jeroen; de Witte, Piet; Mucheto, Samson; Nagelkerke, Nico; Kager, Piet
OBJECTIVE: To evaluate the feasibility of automated malaria detection with the Cell-Dyn 3700 (Abbott Diagnostics, Santa Clara, CA, USA) haematology analyser for diagnosing malaria in northern Namibia. METHODS: From April to June 2003, all patients with a positive blood smear result and a subset of
Ndibazza, Juliet; Webb, Emily L; Lule, Swaib
Background. Helminth and malaria coinfections are common in the tropics. We investigated the hypothesis that prenatal exposure to these parasites might influence susceptibility to infections such as malaria in childhood.Methods. In a birth cohort of 2,345 mother-child pairs in Uganda, maternal...... helminth and malaria infection status was determined during pregnancy, and childhood malaria episodes recorded from birth to age five years. We examined associations between maternal infections and malaria in the offspring.Results. Common maternal infections were hookworm (45%), Mansonella perstans (21......%), Schistosoma mansoni (18%), and Plasmodium falciparum (11%). At age 5 years, 69% of the children were still under follow-up. The incidence of malaria was 34 episodes per 100 child-years, and the mean prevalence of asymptomatic malaria at annual visits was 5.4%. Maternal hookworm and M. perstans infections were...
Syaifudin, M.; Tetriana, D.; Darlina; Nurhayati, S.
Malaria, a plasmodial disease, causes more than one million deaths per year and has a significant public health impact. Improved access to prompt treatment with effective antimalarial drugs need to be conducted for prevention of infection in high risk groups. However, the parasite as causal agent has exhibited a potential danger of wide-spread resistances. This warning has directed attention to the study of alternative methods of protection against the disease, among them is to do the immunization. A deeper understanding of the nature and regulation of protective immune mechanisms against this parasite will facilitate the development of much needed vaccines. Developing a malaria vaccine remains an enormous scientific, technical, and financial challenge. Currently a vaccine is not fully available. Among the practical applications of radiobiological techniques that may be of considerable interest for public health is the use of ionizing radiation in the preparation of vaccines. Convincing data were reported that sporozoites of Plasmodium berghei irradiated with X- or gamma-rays, provide an antigenic stimulus effective to induce a protective immune response in mice and rats against subsequent sporozoite infection. Irradiated parasites are better immunogens than killed ones and although non-infective they are still metabolically active, as shown by continued protein and nucleic acid synthesis. There is a substantial number of data from human studies demonstrating that sporozoites attenuated by radiation are potent inducer of protective immunity and that they are safe and do not give rise to the asexual erythrocytic infections that cause malaria. This vaccine is relatively inexpensive to produce, easy to store, and transportable without refrigeration. A long-term effort and commitment to providing resources must be maintained and increased to achieve the goal of a malaria vaccine candidate where ionizing radiation as a tool to prepare is seemingly feasible. (author)
Yesuf, Elias Ali; Dejene, Tariku
Background Worldwide an estimated 225 million cases and about 800, 000 deaths due to malaria were documented in 2009. Malaria vaccines have been developed as a malaria control strategy. Immune response to these vaccines might be affected by the blood fluke schistosoma which is often co-endemic with malaria in Sub-Saharan Africa where most of phase II and Phase III malaria vaccine trials were conducted.Objectives To systematically search, appraise and synthesize the best available evidence on the effect of schistosoma infection on the immune response to malaria antigens and provide direction to future malaria vaccination trials.Types of participants The review considered studies with above 5 year old individuals as participants.Phenomenon of interest The phenomenon of interest was the presence of schistosoma infectionTypes of outcomes Blood serum levels of Th1 and Th2 specific to Merozoite Surface Proteins 1, 2, and 3 of malaria were considered as primary outcomes. While blood serum levels of IgG1, IgG2, IgG3, IFN-γ, IL-10 and TGF-β directed against Merozoite Surface Proteins were considered as secondary outcomes.Types of studies Studies with any quantitative study designs were considered for inclusion.Search Strategy Any quantitative English language articles published between 1994 and April 2011 were sought using a comprehensive search strategy.Assessment of methodological quality It was done using Joanna Briggs Institutes' Meta Analysis of Statistical Assessment and Review Instrument critical appraisal tools.Data extraction Data extraction was carried out using the Joanna Briggs Institute Meta Analysis of Statistical Assessment and Review Instrument data extraction tool.Data synthesis Meta- analysis was conducted using random effects model with an inverse variance method with RevMan5 software. Heterogeneity between the studies was assessed using ξ test at a p-value of SMD (95% CI), 0.15 (-2.00, 2.31), p=0.89.Similarly a small and statistically not significant
Tompkins, Adrian M; Ermert, Volker
The relative roles of climate variability and population related effects in malaria transmission could be better understood if regional-scale dynamical malaria models could account for these factors. A new dynamical community malaria model is introduced that accounts for the temperature and rainfall influences on the parasite and vector life cycles which are finely resolved in order to correctly represent the delay between the rains and the malaria season. The rainfall drives a simple but physically based representation of the surface hydrology. The model accounts for the population density in the calculation of daily biting rates. Model simulations of entomological inoculation rate and circumsporozoite protein rate compare well to data from field studies from a wide range of locations in West Africa that encompass both seasonal endemic and epidemic fringe areas. A focus on Bobo-Dioulasso shows the ability of the model to represent the differences in transmission rates between rural and peri-urban areas in addition to the seasonality of malaria. Fine spatial resolution regional integrations for Eastern Africa reproduce the malaria atlas project (MAP) spatial distribution of the parasite ratio, and integrations for West and Eastern Africa show that the model grossly reproduces the reduction in parasite ratio as a function of population density observed in a large number of field surveys, although it underestimates malaria prevalence at high densities probably due to the neglect of population migration. A new dynamical community malaria model is publicly available that accounts for climate and population density to simulate malaria transmission on a regional scale. The model structure facilitates future development to incorporate migration, immunity and interventions.
The present study was carried out to investigate the relationship between blood group types and P. falciparum malaria, as well as malaria preventive measures. The venous blood specimens were collected, processed, Giemsa-stained and examined microscopically. ABO groups were determined by agglutination test using ...
The recent increases in malaria mortality rates in Africa ... the world's population at risk of malaria are in Africa. (WHO, 2000). ... understood to be both a disease of poverty and a cause ... anaemia and 8 to 14% of low birth weight in areas with.
in low and middle income countries (1-4). In. 2013, malaria killed over a billion people, mostly in sub-Saharan ... According to the 2016 report,. 27% of the population lives in high transmission areas while 41% ... Similarly several countries have reduced malaria transmission to levels low enough to allow them to embark on ...
Nov 5, 2007 ... consequences of malaria treatment pattern and management strategies in an urban center. Questionnaires were issued ... anopheles mosquitoes as malaria vector are some of the factors militating against prevention and proper management of the .... bush clearing, drainage and gutter control in preventing.
Takken, W.; Knols, B.G.J.
The recently announced call for malaria eradication represents a new page in the history of this disease. This has been triggered by remarkable reductions in malaria resulting from combined application of effective drugs and vector control. However, this strategy is threatened by development of
Hviid, Lars; Barfod, Lea
Although experts in the field have agreed on the malaria vaccine technology roadmap that should be followed (http://www.malariavaccineroadmap.net/), the path towards an effective malaria vaccine remains littered with intellectual and practical pot-holes. The animal models that are currently...
Dec 15, 2009 ... Malaria prevalence studies had been undertaken in many parts of Nigeria but there is probably no data available from the far North Western region. This research study was undertaken to determine the prevalence, monthly distribution of malaria in Sokoto, North Western Nigeria in order to generate base-.
Pukrittayakamee, S.; Krishna, S.; ter Kuile, F.; Wilaiwan, O.; Williamson, D. H.; White, N. J.
We investigated the integrity of the gluconeogenic pathway in severe malaria using alanine metabolism as a measure. Alanine disposition and liver blood flow, assessed by indocyanine green (ICG) clearance, were measured simultaneously in 10 patients with falciparum malaria (six severe and four
There is no established and widely accepted guidelines for clinical management of severe neonatal malaria. The aim of this paper is to raise the alertness of physicians regarding the occurrence of severe malaria in the neonatal period and to describe the treatment modality we adopted (in the absence of an internationally ...
imported or Odyssean malaria from countries such as Swaziland,. Mozambique ... can be administered.⁵ The only .... Treatment. With the introduction of an effective vaccine for Southern Africa .... Being prepared for a malaria infection by packing ... sulfadoxine-pyrimethamine against Plasmodium falciparum in Yemen and.
Use of chloroquine in uncomplicated falciparum malaria chemotherapy: The past, the present and the future. ... regions. It was initially highly effective against the four Plasmodium species (P. falciparum, P. malaria, P. ovale and P. vivax) infecting human. It is also effective against gametocytes except those of P. falciparum.
Malaria prevention is increasingly insecticide based. Dr. John Gimnig, an entomologist with the Division of Parasitic Diseases, CDC, discusses evidence that mosquito resistance to insecticides, which is measured in the laboratory, could compromise malaria prevention in the field. Created: 1/24/2007 by Emerging Infectious Diseases. Date Released: 3/13/2007.
Brabin, B. J.; Romagosa, C.; Abdelgalil, S.; Menéndez, C.; Verhoeff, F. H.; McGready, R.; Fletcher, K. A.; Owens, S.; D'Alessandro, U.; Nosten, F.; Fischer, P. R.; Ordi, J.
The human placenta is an ideal site for the accumulation of Plasmodium falciparum malaria parasites, and as a consequence serious health problems arise for the mother and her baby. The pathogenesis of placental malaria is only partially understood, but it is clear that it leads to a distinct
Carlton, Jane M; Sullivan, Steven A
The Plasmodium genus has evolved over time and across hosts, complexifying our understanding of malaria. In a recent Nature paper, Rutledge et al. (2017) describe the genome sequences of three major human malaria parasite species, providing insight into Plasmodium evolution and raising the question of how many species there are. Copyright © 2017 Elsevier Inc. All rights reserved.
Kooij, Taco W.A.
The aim of the studies described in this thesis was to investigate the genome organization of rodent malaria parasites (RMPs) and compare the organization and gene content of the genomes of RMPs and the human malaria parasite P. falciparum. The release of the complete genome sequence of P.
Malaria is the principal cause of morbidity and mortality in Mozambique and is considered a major impediment to development. The effectiveness of any malaria control program depends on reliable data delivered in timely fashion, something that is currently lacking in the nation's health service. This grant will allow the ...
Malaria is the principal cause of morbidity and mortality in Mozambique and is considered a major impediment to development. The effectiveness of any malaria control program depends on reliable data delivered in timely fashion, something that is currently lacking in the nation's health service. This grant will allow the ...
Oria, Prisca A.
Chapter 1 presents the background information relevant to the subject matter and methods of this thesis. These include the application of social and behavioural sciences in malaria control, the SolarMal project and malaria in Kenya. It also presents the research objective, question and design
Mahende, Coline; Ngasala, Billy; Lusingu, John
with fever and/or history of fever in the previous 48 h attending outpatient clinics. Blood samples were collected for identification of Plasmodium falciparum infection using histidine-rich-protein-2 (HRP-2)-based malaria RDT, light microscopy and conventional PCR. Results: A total of 867 febrile patients......Background: Rapid diagnostic tests (RDT) and light microscopy are still recommended for diagnosis to guide the clinical management of malaria despite difficult challenges in rural settings. The performance of these tests may be affected by several factors, including malaria prevalence and intensity...... of transmission. The study evaluated the diagnostic performance of malaria RDT, light microscopy and polymerase chain reaction (PCR) in detecting malaria infections among febrile children at outpatient clinic in Korogwe District, northeastern Tanzania. Methods: The study enrolled children aged 2-59 months...
Background: Despite the rapid expansion of malaria into highland areas of Ethiopia and the movement of malaria inexperienced people to endemic areas, there is no enough information about how highland communities perceive malaria. Objective: To assess communities' awareness of malaria and its mosquito vector in ...
Transferring the Malaria Epidemic Prediction Model to Users in East Africa. In the highlands of East Africa, epidemic malaria is an emerging climate-related hazard that urgently needs addressing. Malaria incidence increased by 337% during the 1987 epidemic in Rwanda. In Tanzania, Uganda and Kenya, malaria incidence ...
Malaria has been a plague for human mankind. Each year roughly 125 million pregnancies are at risk for malaria infection. This thesis demonstrates the detrimental effects of malaria in pregnancy on the mother and the baby. To determine the effects of malaria in pregnancy on birth outcomes, accurate
Malaria infection during pregnancy in area of stable transmission. ... (LBW), a leading cause of neonatal death in areas of stable malaria transmission. ... areas of stable malaria transmission and the effective strategies for prevention and control. Keywords: malaria, pregnancy, semi-immune women, anaemia, low birthweight
Taylor, Walter R J; Cañon, Viviam; White, Nicholas J
Lung involvement in malaria has been recognized for more than 200 hundred years, yet our knowledge of its pathogenesis and management is limited. Pulmonary edema is the most severe form of lung involvement. Increased alveolar capillary permeability leading to intravascular fluid loss into the lungs is the main pathophysiologic mechanism. This defines malaria as another cause of acute lung injury (ALI) and acute respiratory distress syndrome (ARDS).Pulmonary edema has been described most often in non-immune individuals with Plasmodium falciparum infections as part of a severe systemic illness or as the main feature of acute malaria. P.vivax and P.ovale have also rarely caused pulmonary edema.Clinically, patients usually present with acute breathlessness that can rapidly progress to respiratory failure either at disease presentation or, interestingly, after treatment when clinical improvement is taking place and the parasitemia is falling. Pregnant women are particularly prone to developing pulmonary edema. Optimal management of malaria-induced ALI/ARDS includes early recognition and diagnosis. Malaria must always be suspected in a returning traveler or a visitor from a malaria-endemic country with an acute febrile illness. Slide microscopy and/or the use of rapid antigen tests are standard diagnostic tools. Malaria must be treated with effective drugs, but current choices are few: e.g. parenteral artemisinins, intravenous quinine or quinidine (in the US only). A recent trial in adults has shown that intravenous artesunate reduces severe malaria mortality by a third compared with adults treated with intravenous quinine. Respiratory compromise should be managed on its merits and may require mechanical ventilation.Patients should be managed in an intensive care unit and particular attention should be paid to the energetic management of other severe malaria complications, notably coma and acute renal failure. ALI/ARDS may also be related to a coincidental bacterial
Shoda, M; Shimizu, K; Nagano, M; Ishii, M
Plasmodium falciparum malaria is the most dangerous infection for seafarers in West Africa. In December 1998, five cases of this infection occurred among Japanese seafarers in West Africa, two of them died, one on board ship, and another died five days after the admission to the hospital in Reunion island, East Africa. Six other cases of falciparum malaria infection occurred among Japanese seafarers on another ship in December 1999. Three infected persons were admitted to hospitals in Abidjan (Ivory Coast) and Point Noire (Congo). In Japan, over 100 cases of imported malaria were recorded each year during the period from 1990 to 1997, and about 40% of these cases were falciparum infections. It is not known how many of them occurred among seafarers. We estimate that at least 5% of all malaria cases in Japan are seafarers. Measures to protect crews of ships against malaria are discussed.
Munzir, Said; Nasir, Muhammad; Ramli, Marwan
Malaria is a disease caused by an amoeba (single-celled animal) type of plasmodium where anopheles mosquito serves as the carrier. This study examines the optimal control problem of malaria disease spread based on Aron and May (1982) SIR type models and seeks the optimal solution by minimizing the prevention of the spreading of malaria by vaccine. The aim is to investigate optimal control strategies on preventing the spread of malaria by vaccination. The problem in this research is solved using analytical approach. The analytical method uses the Pontryagin Minimum Principle with the symbolic help of MATLAB software to obtain optimal control result and to analyse the spread of malaria with vaccination control.
Cerebral malaria (CM) is a severe neurological complication of malaria infection that results from interrelated pathologies. Despite extensive research efforts, the mechanism of the disease is not completely understood. Clinical studies, postmortem analysis, and animal models have been the main research arenas in CM. In this thesis, shotgun proteomics approach was used to further understand the pathology of human and experimental CM. The mechanism by which CM turns fatal is yet to be identified. A clinical proteomics study was conducted on pooled plasma samples from children with reversible or fatal CM from the Gambia. The results show that depletion of coagulation factors and increased levels of circulating proteasomes are associated with fatal pediatric CM. This data suggests that the ongoing coagulation during CM might be a disseminated intravascular coagulation state that eventually causes depletion of the coagulation factors leading to petechial hemorrhages. In addition, the mechanism(s) by which blood transfusion benefits CM in children was investigated. To that end, the concentration and multimerization pattern of von-willebrand factor, and the concentration of haptoglobin in the plasma of children with CM who received blood transfusions were measured. In addition to clinical studies, experimental cerebral malaria (ECM) in mice has been long used as a model for the disease. A shotgun proteomics workflow was optimized to identify the proteomic signature of the brain tissue of mice with ECM.Because of the utmost importance of membrane proteins in the pathology of the disease, sample fractionation and filter aided sample preparation were used to recover them. The proteomic signature of the brains of mice infected with P. berghei ANKA that developed neurological syndrome, mice infected with P. berghei NK56 that developed severe malaria but without neurological signs, and non-infected mice, were compared to identify CM specific proteins. Among the differentially
Tri Rini Puji Lestari
health official Malaria Center, and community leaders who observe malaria. Retrieval of data time is 10 – 16 April 2011 by in-depth interviews. It was found that malaria control programs have been implemented by the Departement of Health North Maluku Province, but have not been able to effectively reduce malaria morbidity. This is because malaria control is performed is not comprehensive. Handling is more directed to break the chain transmission to human, their habitats have not been touched up. Key words: Control of malaria, millennium development goals, malaria morbidity
Full Text Available Malaria is one of the most widespread parasitic infection in Asian countries affecting the poor of the poor. In an effort to develop an effective vaccine for the treatment of malaria, various attempts are being made worldwide. If successful, such a vaccine can be effective for treatment of both Plasmodium vivax and Plasmodium falciparum. This would also be able to avoid complications such as drug resistance, resistance to insecticides, nonadherence to the treatment schedule, and eventually high cost of treatment in the resource-limited settings. In the current compilation, the details from the literature were collected by using PubMed and Medline as search engines and searched for terms such as malaria, vaccine, and malaria treatment. This review collates and provides glimpses of the information on the recent malaria vaccine development. The reader will be taken through the historical perspective followed by the approaches to the malaria vaccine development from pre-erythrocytic stage vaccines, asexual stage vaccines, transmission blocking vaccines, etc. Looking at the current scenario of the malaria and treatment strategies, it is an absolute need of an hour that an effective malaria vaccine should be developed. This would bring a revolutionary breakthrough in the treatment modalities especially when there is increasing emergence of resistance to existing drug therapy. It would be of great purpose to serve those living in malaria endemic region and also for travelers which are nonimmune and coming to malaria endemic region. As infection by P. vivax is more prevalent in India and other Asian subcontinent and is often prominent in areas where elimination is being attempted, special consideration is required of the role of vaccines in blocking transmission, regardless of the stages being targeted. Development of vaccines is feasible but with the support of private sector and government organization in terms of regulatory and most importantly
Tine, Roger Ck; Ndiaye, Pascal; Ndour, Cheikh T
Community case management of malaria (CCMm) and seasonal malaria chemoprevention (SMC) are anti-malarial interventions that can lead to substantial reduction in malaria burden acting in synergy. However, little is known about the social acceptability of these interventions. A study was undertaken...... to assess whether combining the interventions would be an acceptable approach to malaria control for community health workers (CHWs)....
Judy A Omumbo
Full Text Available Rational decision making on malaria control depends on an understanding of the epidemiological risks and control measures. National Malaria Control Programmes across Africa have access to a range of state-of-the-art malaria risk mapping products that might serve their decision-making needs. The use of cartography in planning malaria control has never been methodically reviewed.An audit of the risk maps used by NMCPs in 47 malaria endemic countries in Africa was undertaken by examining the most recent national malaria strategies, monitoring and evaluation plans, malaria programme reviews and applications submitted to the Global Fund. The types of maps presented and how they have been used to define priorities for investment and control was investigated.91% of endemic countries in Africa have defined malaria risk at sub-national levels using at least one risk map. The range of risk maps varies from maps based on suitability of climate for transmission; predicted malaria seasons and temperature/altitude limitations, to representations of clinical data and modelled parasite prevalence. The choice of maps is influenced by the source of the information. Maps developed using national data through in-country research partnerships have greater utility than more readily accessible web-based options developed without inputs from national control programmes. Although almost all countries have stratification maps, only a few use them to guide decisions on the selection of interventions allocation of resources for malaria control.The way information on the epidemiology of malaria is presented and used needs to be addressed to ensure evidence-based added value in planning control. The science on modelled impact of interventions must be integrated into new mapping products to allow a translation of risk into rational decision making for malaria control. As overseas and domestic funding diminishes, strategic planning will be necessary to guide appropriate
Omumbo, Judy A; Noor, Abdisalan M; Fall, Ibrahima S; Snow, Robert W
Rational decision making on malaria control depends on an understanding of the epidemiological risks and control measures. National Malaria Control Programmes across Africa have access to a range of state-of-the-art malaria risk mapping products that might serve their decision-making needs. The use of cartography in planning malaria control has never been methodically reviewed. An audit of the risk maps used by NMCPs in 47 malaria endemic countries in Africa was undertaken by examining the most recent national malaria strategies, monitoring and evaluation plans, malaria programme reviews and applications submitted to the Global Fund. The types of maps presented and how they have been used to define priorities for investment and control was investigated. 91% of endemic countries in Africa have defined malaria risk at sub-national levels using at least one risk map. The range of risk maps varies from maps based on suitability of climate for transmission; predicted malaria seasons and temperature/altitude limitations, to representations of clinical data and modelled parasite prevalence. The choice of maps is influenced by the source of the information. Maps developed using national data through in-country research partnerships have greater utility than more readily accessible web-based options developed without inputs from national control programmes. Although almost all countries have stratification maps, only a few use them to guide decisions on the selection of interventions allocation of resources for malaria control. The way information on the epidemiology of malaria is presented and used needs to be addressed to ensure evidence-based added value in planning control. The science on modelled impact of interventions must be integrated into new mapping products to allow a translation of risk into rational decision making for malaria control. As overseas and domestic funding diminishes, strategic planning will be necessary to guide appropriate financing for malaria
Chuang, Ting-Wu; Soble, Adam; Ntshalintshali, Nyasatu; Mkhonta, Nomcebo; Seyama, Eric; Mthethwa, Steven; Pindolia, Deepa; Kunene, Simon
Swaziland aims to eliminate malaria by 2020. However, imported cases from neighbouring endemic countries continue to sustain local parasite reservoirs and initiate transmission. As certain weather and climatic conditions may trigger or intensify malaria outbreaks, identification of areas prone to these conditions may aid decision-makers in deploying targeted malaria interventions more effectively. Malaria case-surveillance data for Swaziland were provided by Swaziland's National Malaria Control Programme. Climate data were derived from local weather stations and remote sensing images. Climate parameters and malaria cases between 2001 and 2015 were then analysed using seasonal autoregressive integrated moving average models and distributed lag non-linear models (DLNM). The incidence of malaria in Swaziland increased between 2005 and 2010, especially in the Lubombo and Hhohho regions. A time-series analysis indicated that warmer temperatures and higher precipitation in the Lubombo and Hhohho administrative regions are conducive to malaria transmission. DLNM showed that the risk of malaria increased in Lubombo when the maximum temperature was above 30 °C or monthly precipitation was above 5 in. In Hhohho, the minimum temperature remaining above 15 °C or precipitation being greater than 10 in. might be associated with malaria transmission. This study provides a preliminary assessment of the impact of short-term climate variations on malaria transmission in Swaziland. The geographic separation of imported and locally acquired malaria, as well as population behaviour, highlight the varying modes of transmission, part of which may be relevant to climate conditions. Thus, the impact of changing climate conditions should be noted as Swaziland moves toward malaria elimination.
Omumbo, Judy A.; Noor, Abdisalan M.; Fall, Ibrahima S.; Snow, Robert W.
Introduction Rational decision making on malaria control depends on an understanding of the epidemiological risks and control measures. National Malaria Control Programmes across Africa have access to a range of state-of-the-art malaria risk mapping products that might serve their decision-making needs. The use of cartography in planning malaria control has never been methodically reviewed. Materials and Methods An audit of the risk maps used by NMCPs in 47 malaria endemic countries in Africa was undertaken by examining the most recent national malaria strategies, monitoring and evaluation plans, malaria programme reviews and applications submitted to the Global Fund. The types of maps presented and how they have been used to define priorities for investment and control was investigated. Results 91% of endemic countries in Africa have defined malaria risk at sub-national levels using at least one risk map. The range of risk maps varies from maps based on suitability of climate for transmission; predicted malaria seasons and temperature/altitude limitations, to representations of clinical data and modelled parasite prevalence. The choice of maps is influenced by the source of the information. Maps developed using national data through in-country research partnerships have greater utility than more readily accessible web-based options developed without inputs from national control programmes. Although almost all countries have stratification maps, only a few use them to guide decisions on the selection of interventions allocation of resources for malaria control. Conclusion The way information on the epidemiology of malaria is presented and used needs to be addressed to ensure evidence-based added value in planning control. The science on modelled impact of interventions must be integrated into new mapping products to allow a translation of risk into rational decision making for malaria control. As overseas and domestic funding diminishes, strategic planning will be
Koita, Kadiatou; Novotny, Joseph; Kunene, Simon; Zulu, Zulizile; Ntshalintshali, Nyasatu; Gandhi, Monica; Gosling, Roland
Swaziland has made great progress towards its goal of malaria elimination by 2015. However, malaria importation from neighbouring high-endemic Mozambique through Swaziland's eastern border remains a major factor that could prevent elimination from being achieved. In order to reach elimination, Swaziland must rapidly identify and treat imported malaria cases before onward transmission occurs. A nationwide formative assessment was conducted over eight weeks to determine if the imported cases of malaria identified by the Swaziland National Malaria Control Programme could be linked to broader social networks and to explore methods to access these networks. Using a structured format, interviews were carried out with malaria surveillance agents (6), health providers (10), previously identified imported malaria cases (19) and people belonging to the networks identified through these interviews (25). Most imported malaria cases were Mozambicans (63%, 12/19) making a living in Swaziland and sustaining their families in Mozambique. The majority of imported cases (73%, 14/19) were labourers and self-employed contractors who travelled frequently to Mozambique to visit their families and conduct business. Social networks of imported cases with similar travel patterns were identified through these interviews. Nearly all imported cases (89%, 17/19) were willing to share contact information to enable network members to be interviewed. Interviews of network members and key informants revealed common congregation points, such as the urban market places in Manzini and Malkerns, as well as certain bus stations, where people with similar travel patterns and malaria risk behaviours could be located and tested for malaria. This study demonstrated that imported cases of malaria belonged to networks of people with similar travel patterns. This study may provide novel methods for screening high-risk groups of travellers using both snowball sampling and time-location sampling of networks to
Emmanuel, Benjamin; Kawira, Esther; Ogwang, Martin D; Wabinga, Henry; Magatti, Josiah; Nkrumah, Francis; Neequaye, Janet; Bhatia, Kishor; Brubaker, Glen; Biggar, Robert J; Mbulaiteye, Sam M
African Burkitt lymphoma is an aggressive B-cell, non-Hodgkin lymphoma linked to Plasmodium falciparum malaria. Malaria biomarkers related to onset of African Burkitt lymphoma are unknown. We correlated age-specific patterns of 2,602 cases of African Burkitt lymphoma (60% male, mean ± SD age = 7.1 ± 2.9 years) from Uganda, Ghana, and Tanzania with malaria biomarkers published from these countries. Age-specific patterns of this disease and mean multiplicity of P. falciparum malaria parasites, defined as the average number of distinct genotypes per positive blood sample based on the merozoite surface protein-2 assessed by polymerase chain reaction, were correlated and both peaked between 5 and 9 years. This pattern, which was strong and consistent across regions, contrasted parasite prevalence, which peaked at 2 years and decreased slightly, and geometric mean parasite density, which peaked between 2 and 3 years and decreased sharply. Our findings suggest that concurrent infection with multiple malaria genotypes may be related to onset of African Burkitt lymphoma.
With the adoption of the Global Malaria Action Plan, several countries are moving from malaria control towards elimination and eradication. However, the sustainability of some of the approaches taken may be questionable. Here, an overview of malaria control and elimination strategies is provided and the sustainability of each in context of vector- and parasite control is assessed. From this, it can be concluded that transdisciplinary approaches are essential for sustained malaria control and elimination in malaria-endemic communities. PMID:23268712
Full Text Available Abstract With the adoption of the Global Malaria Action Plan, several countries are moving from malaria control towards elimination and eradication. However, the sustainability of some of the approaches taken may be questionable. Here, an overview of malaria control and elimination strategies is provided and the sustainability of each in context of vector- and parasite control is assessed. From this, it can be concluded that transdisciplinary approaches are essential for sustained malaria control and elimination in malaria-endemic communities.
In 1978 the concept of primary health care was adopted by 116 countries at Alma Ata, yet the negative impact of structural readjustment programs in Africa and South America could be felt due to the cuts in expenditures on health, education, and social matters. The result is a resurgence of communicable diseases such as malaria and tuberculosis. Another factor in this resurgence is extreme poverty. In 1994 over 1000 people died in Rajasthan, India, of a malaria epidemic, and during the same time in Delhi over 300 deaths were attributed to hemorrhagic dengue fever. Malariogenic and tuberculous conditions continue to flourish owing to distorted development patterns and commercialization of medical care as public health and community health services are being replaced by profit-oriented curative care, 80% of which is in private hands. This has resulted in spiraling medical care costs and rural indebtedness. Socioeconomic deprivation in developing countries threatens TB control. Factors contributing to the spread of TB were established in 1899 and are still valid in India and other developing countries: TB contamination of air, inadequate food, overcrowded dwelling, and low state of physical health. Even in developed countries TB is on the rise: there were 172 cases in 1991 in England vs. 305 cases in 1993, half of them among immigrants. The increase occurred in the poorest 30% of the population. The World Bank is providing loans for a revised TB and malaria strategy, and the Disability Adjusted Life Year has been used to identify the greatest burden of diseases. On the other hand, the Indian National Health Policy has not been revised since 1983. Priority must be given to those living in extreme poverty to curb the resurgence of once controlled diseases.
Lin, Jinfeng; Huang, Xiaoying; Qin, Gang; Zhang, Suyan; Sun, Weiwei; Wang, Yadong; Ren, Ke; Xu, Junxian; Han, Xudong
This study was designed to evaluate the efficacy of exchange transfusion in patients with severe imported falciparum malaria. Twelve patients who met the diagnostic criteria for severe malaria were treated with exchange transfusion 14 times according to a conventional anti-malarial treatment. This study evaluated the efficacy of exchange transfusion for severe imported falciparum malaria. Clinical data of severe imported falciparum malaria patients admitted to the intensive care unit (ICU) of Nantong Third People's Hospital from January 2007 to December 2016 were investigated in this retrospective study. Patients were divided into the intervention group, which received exchange transfusion, and the control group. This study assessed parasite clearance and outcomes of the two groups, and levels of erythrocytes, haemoglobin, platelets, coagulation, liver function, lactate, C-reactive protein, and procalcitonin, before and after exchange transfusion in the intervention group. There was no significant difference in the severity of admitted patients. Exchange transfusion was successfully applied 14 times in the intervention group. Differences in the levels of erythrocytes, haemoglobin and platelets did not reach statistical significance. Exchange transfusion improved coagulation, liver function, lactic acid, C-reactive protein, and procalcitonin. No differences were observed in parasite clearance, ICU and hospital length of stay, in-hospital mortality, and costs of hospitalization between the two groups. Exchange transfusion as adjunctive therapy for severe malaria was observed to be safe in this setting. Exchange transfusion can improve liver function and coagulation and reduce inflammation, but it failed to improve parasite clearance and the outcomes of severe imported falciparum malaria in this case series.
Full Text Available BACKGROUND: An epidemiological and entomological study was carried out in Balaghat district, Madhya Pradesh, India to understand the dynamics of forest malaria transmission in a difficult and hard to reach area where indoor residual spray and insecticide treated nets were used for vector control. METHODS: This community based cross-sectional study was undertaken from January 2010 to December 2012 in Baihar and Birsa Community Health Centres of district Balaghat for screening malaria cases. Entomological surveillance included indoor resting collections, pyrethrum spray catches and light trap catches. Anophelines were assayed by ELISA for detection of Plasmodium circumsporozoite protein. FINDINGS: Plasmodium falciparum infection accounted for >80% of all infections. P. vivax 16.5%, P. malariae 0.75% and remaining were mixed infections of P. falciparum, P. vivax and P. malariae. More than, 30% infections were found in infants under 6 months of age. Overall, an increasing trend in malaria positivity was observed from 2010 to 2012 (chi-square for trend = 663.55; P<0.0001. Twenty five Anopheles culicifacies (sibling species C, D and E were positive for circumsporozoite protein of P. falciparum (44% and P. vivax (56%. Additionally, 2 An. fluviatilis, were found positive for P. falciparum and 1 for P. vivax (sibling species S and T. An. fluviatilis sibling species T was found as vector in forest villages for the first time in India. CONCLUSION: These results showed that the study villages are experiencing almost perennial malaria transmission inspite of indoor residual spray and insecticide treated nets. Therefore, there is a need for new indoor residual insecticides which has longer residual life or complete coverage of population with long lasting insecticide treated nets or both indoor residual spray and long lasting bed nets for effective vector control. There is a need to undertake a well designed case control study to evaluate the efficacy
Full Text Available A longitudinal epidemiological and entomological study was carried out in Ocamo, Upper Orinoco River, between January 1994 and February 1995 to understand the dynamics of malaria transmission in this area. Malaria transmission occurs throughout the year with a peak in June at the beginning of the rainy season. The Annual Parasite Index was 1,279 per 1,000 populations at risk. Plasmodium falciparum infections accounted for 64% of all infections, P. vivax for 28%, and P. malariae for 4%. Mixed P. falciparum/P. vivax infections were diagnosed in 15 people representing 4% of total cases. Children under 10 years accounted for 58% of the cases; the risk for malaria in this age group was 77% higher than for those in the greater than 50 years age group. Anopheles darlingi was the predominant anopheline species landing on humans indoors with a biting peak between midnight and dawn. A significant positive correlation was found between malaria monthly incidence and mean number of An. darlingi caught. There was not a significant relationship between mean number of An. darlingi and rainfall or between incidence and rainfall. A total of 7295 anophelines were assayed by ELISA for detection of Plasmodium circumsporozoite (CS protein. Only An. darlingi (55 was positive for CS proteins of P. falciparum (0.42%, P. malariae (0.25%, and P. vivax-247 (0.1%. The overall estimated entomological inoculation rate was 129 positive bites/person/year. The present study was the first longitudinal entomological and epidemiological study conducted in this area and set up the basic ground for subsequent intervention with insecticide-treated nets.
Dondorp, Arjen M; Day, Nick P J
In the SEAQUAMAT trial, parenteral artesunate was shown to be associated with a considerably lower mortality than quinine, and is now the recommended treatment for severe malaria in low-transmission areas and in the second and third trimesters of pregnancy. A trial is underway to establish its role in African children. The development of artesunate suppositories may provide the means to treat patients with severe disease in remote rural settings, potentially buying the time needed to reach a health care facility. The increasing availability of basic intensive care facilities in developing countries also has the potential to further reduce mortality.
Ofori Michael F
Full Text Available Abstract Background Severe anaemia (SA, intravascular haemolysis (IVH and respiratory distress (RD are severe forms of Plasmodium falciparum malaria, with RD reported to be of prognostic importance in African children with malarial anaemia. Complement factors have been implicated in the mechanism leading to excess anaemia in acute P. falciparum infection. Methods The direct Coombs test (DCT and flow cytometry were used to investigate the mean levels of RBC-bound complement fragments (C3d and C3bαβ and the regulatory proteins [complement receptor 1 (CD35 and decay accelerating factor (CD55] in children with discrete clinical forms of P. falciparum malaria. The relationship between the findings and clinical parameters including coma, haemoglobin (Hb levels and RD were investigated. Results Of the 484 samples tested, 131(27% were positive in DCT, out of which 115/131 (87.8% were positive for C3d alone while 16/131 (12.2% were positive for either IgG alone or both. 67.4% of the study population were below 5 years of age and DCT positivity was more common in this age group relative to children who were 5 years or older (Odds ratio, OR = 3.8; 95%CI, 2.2–6.7, p Conclusion These results suggest that complement activation contributed to anaemia in acute childhood P. falciparum malaria, possibly through induction of erythrophagocytosis and haemolysis. In contrast to other studies, this study did not find association between levels of the complement regulatory proteins, CD35 and CD55 and malarial anaemia. These findings suggest that complement activation could also be involved in the pathogenesis of RD but larger studies are needed to confirm this finding.
Islam, Nazrul; Bonovas, Stefanos; Nikolopoulos, Georgios K
Bangladesh is one of the four major malaria-endemic countries in South-East Asia having approximately 34% of its population at risk of malaria. This paper aims at providing an overview of the malaria situation in this country. Relevant information was retrieved from published articles and reports in PubMed and Google Scholar. Malaria in Bangladesh is concentrated in 13 districts with a prevalence ranging between 3.1% and 36%, and is mostly caused by Plasmodium falciparum. Geographical conditions pose a potential risk for Plasmodium knowlesi malaria. Resistance to a number of drugs previously recommended for treatment has been reported. Low socio-economic status, poor schooling and close proximity to water bodies and forest areas comprise important risk factors. Despite the significant steps in Long Lasting Insecticide Net (LLIN)/Insecticide Treated Net (ITN) coverage in Bangladesh, there are still many challenges including the extension of malaria support to the remote areas of Bangladesh, where malaria prevalence is higher, and further improvements in the field of referral system and treatment. Copyright © 2013 Elsevier Ltd. All rights reserved.
Dev, Vas; Adak, Tridibes; Singh, Om P; Nanda, Nutan; Baidya, Bimal K
Malaria is a major public health problem in Tripura and focal disease outbreaks are of frequent occurrence. The state is co-endemic for both Plasmodium falciparum and P. vivax and transmission is perennial and persistent. The present study was aimed to review data on disease distribution to prioritize high-risk districts, and to study seasonal prevalence of disease vectors and their bionomical characteristics to help formulate vector species-specific interventions for malaria control. Data on malaria morbidity in the State were reviewed retrospectively (2008-2012) for understanding disease distribution and transmission dynamics. Cross-sectional mass blood surveys were conducted in malaria endemic villages of South Tripura district to ascertain the prevalence of malaria and proportions of parasite species. Mosquito collections were made in human dwellings of malaria endemic villages aiming at vector incrimination and to study relative abundance, resting and feeding preferences, and their present susceptibility status to DDT. The study showed that malaria was widely prevalent and P. falciparum was the predominant infection (>90%), the remaining were P. vivax cases. The disease distribution, however, was uneven with large concentration of cases in districts of South Tripura and Dhalai coinciding with vast forest cover and tribal populations. Both Anopheles minimus s.s. and An. baimaii were recorded to be prevalent and observed to be highly anthropophagic and susceptible to DDT. Of these, An. minimus was incriminated (sporozoite infection rate 4.92%), and its bionomical characteristics revealed this species to be largely indoor resting and endophagic. For effective control of malaria in the state, it is recommended that diseases surveillance should be robust, and vector control interventions including DDT spray coverage, mass distribution of insecticide-treated nets/ long-lasting insecticidal nets should be intensified prioritizing population groups most at risk to
Colombian professor Manuel Patarroyo developed a new malaria vaccine (SPF66). In February 1995, WHO and the Colombian government agreed to establish a manufacturing plant in Colombia for mass production of SPF66. This vaccine is likely to be available to persons in Africa, where 90% of all annual global cases live. In fact, Africa witnesses one million of 1.5 million annual malaria cases. Many children die from malaria. An extensive clinical trial of the SPF66 vaccine in Colombia achieved a 22-77% protection rate. The young and the very old had the high protection rates. A series of human clinical trials in the Gambia and Tanzania indicate that SPF66 produces a strong immune response against malaria without any harmful side effects. The results of field tests in the Gambia and Thailand and of trials in Colombia are expected in 1995. If the vaccine could reduce the incidence of malaria by just 50%, the lives of as many as 500,000 African children could be saved. SPF66 contains a combination of synthetic peptides (=or 2 amino acids). Mass production would make it affordable (estimated $5/injection). At least five other malaria vaccines hold promise and are ready for human testing in endemic countries. SPF66 is approximately three years ahead of all other promising malaria vaccines. 20 more vaccines are in the development stage. The large scale production of SPF66 in Colombia could begin within three years. Professor Patarroyo has financed his 12-year-old research himself because he wants to protect the lives of persons in developing countries. In 1992, the Congo's president petitioned the international community at the WHO summit in Amsterdam to join the fight against malaria since it is now in a position to defeat malaria since it finished the cold war.
Rosas-Aguirre, Angel; Gamboa, Dionicia; Manrique, Paulo; Conn, Jan E; Moreno, Marta; Lescano, Andres G; Sanchez, Juan F; Rodriguez, Hugo; Silva, Hermann; Llanos-Cuentas, Alejandro; Vinetz, Joseph M
Malaria in Peru, dominated by Plasmodium vivax, remains a public health problem. The 1990s saw newly epidemic malaria emerge, primarily in the Loreto Department in the Amazon region, including areas near to Iquitos, the capital city, but sporadic malaria transmission also occurred in the 1990s-2000s in both north-coastal Peru and the gold mining regions of southeastern Peru. Although a Global Fund-supported intervention (PAMAFRO, 2005-2010) was temporally associated with a decrease of malaria transmission, from 2012 to the present, both P. vivax and Plasmodium falciparum malaria cases have rapidly increased. The Peruvian Ministry of Health continues to provide artemesinin-based combination therapy for microscopy-confirmed cases of P. falciparum and chloroquine-primaquine for P. vivax Malaria transmission continues in remote areas nonetheless, where the mobility of humans and parasites facilitates continued reintroduction outside of ongoing surveillance activities, which is critical to address for future malaria control and elimination efforts. Ongoing P. vivax research gaps in Peru include the following: identification of asymptomatic parasitemics, quantification of the contribution of patent and subpatent parasitemics to mosquito transmission, diagnosis of nonparasitemic hypnozoite carriers, and implementation of surveillance for potential emergence of chloroquine- and 8-aminoquinoline-resistant P. vivax Clinical trials of tafenoquine in Peru have been promising, and glucose-6-phosphate dehydrogenase deficiency in the region has not been observed to be a limitation to its use. Larger-scale challenges for P. vivax (and malaria in general) in Peru include logistical difficulties in accessing remote riverine populations, consequences of government policy and poverty trends, and obtaining international funding for malaria control and elimination. © The American Society of Tropical Medicine and Hygiene.
Pan, W. K.; Zaitchik, B. F.; Pizzitutti, F.; Berky, A.; Feingold, B.; Mena, C.; Janko, M.
Reported cases of malaria in the western Amazon regions of Peru, Colombia and Ecuador have more than tripled since 2011. Responding to this epidemic has been challenging given large-scale environmental impacts and demographic changes combined with changing financial and political priorities. In Peru alone, malaria cases increased 5-fold since 2011. Reasons include changes in the Global Malaria Fund, massive flooding in 2012, the "mega" El Nino in 2016, and continued natural resource extraction via logging and mining. These challenges prompted the recent creation of the Malaria Cero program in 2017 with the goal to eradicate malaria by 2021. To assist in malaria eradiation, a team of investigators supported by NASA have been developing an Early Warning System for Malaria. The system leverages demographic, epidemiological, meteorological and land use/cover data to develop a four-component system that will improve detection of malaria across the western Amazon Basin. System components include a land data assimilation system (LDAS) to estimate past and future hydrological states and flux, a seasonal human population model to estimate population at risk and spatial connectivity to high risk transmission areas, a sub-regional statistical model to identify when and where observed malaria cases have exceeded those expected, and an Agent Based Model (ABM) to integrate human, environmental, and entomological transmission dynamics with potential strategies for control. Data include: daily case detection reports between 2000 and 2017 from all health posts in the region of Loreto in the northern Peruvian Amazon; LDAS outputs (precipitation, temperature, humidity, solar radiation) at a 1km and weekly scale; satellite-derived estimates of land cover; and human population size from census and health data. This presentation will provide an overview of components, focusing on how the system identifies an outbreak and plans for technology transfer.
Okonko, I. O.
Full Text Available This study reports the prevalence of malaria caused by plasmodium between genders in Abeokuta, the capital city of Ogun State located in the forest zone of southwestern Nigeria between January 2002 and December 2004. Blood film examination for malaria parasites in 708 patients; 366 males and 342 females. Microscopic examination of thick films techniques was employed for this study. Of the 708 (100% patients examined, 577 (81.5% were Plasmodium-positive. A high malaria parasite prevalence rate of 81.5% was noted in this study. Female subjects were more infected (42.4% than males (41.9% however, there was no significant difference in the sex of the subjects studied (p=0.05. A high malaria parasite prevalence rate of 86.9% was noted in samples collected in year 2003 than in other years studied. There was significant difference in the years under study (p=0.05. This study shows that a good percentage of people were infested by malaria Plasmodium. This could be attributed to lack of adequate accommodation and poor sanitary conditions in the area under study. Although several efforts have been made to effectively control the high incidence of malaria in Nigeria, these have been largely unsuccessful due to a number of reasons such as irrigated urban agriculture which can be the malaria vector’s breeding ground in the city, stagnant gutters and swamps in our environment where mosquitoes breed in millions, and lack of political will and commitment of the government in its disease management program, low awareness of the magnitude of malaria problem, poor health practices by individuals and communities and resistance to drugs. Therefore, future interventions in Nigeria should be directed toward controlling malaria in the context of a moderate transmission setting; thus, large-scale distribution of insecticide-treated nets or widespread use of indoor residual spraying may be less cost-effective than enhanced surveillance with effective case management or
Rosas-Aguirre, Angel; Gamboa, Dionicia; Manrique, Paulo; Conn, Jan E.; Moreno, Marta; Lescano, Andres G.; Sanchez, Juan F.; Rodriguez, Hugo; Silva, Hermann; Llanos-Cuentas, Alejandro; Vinetz, Joseph M.
Malaria in Peru, dominated by Plasmodium vivax, remains a public health problem. The 1990s saw newly epidemic malaria emerge, primarily in the Loreto Department in the Amazon region, including areas near to Iquitos, the capital city, but sporadic malaria transmission also occurred in the 1990s–2000s in both north-coastal Peru and the gold mining regions of southeastern Peru. Although a Global Fund-supported intervention (PAMAFRO, 2005–2010) was temporally associated with a decrease of malaria transmission, from 2012 to the present, both P. vivax and Plasmodium falciparum malaria cases have rapidly increased. The Peruvian Ministry of Health continues to provide artemesinin-based combination therapy for microscopy-confirmed cases of P. falciparum and chloroquine–primaquine for P. vivax. Malaria transmission continues in remote areas nonetheless, where the mobility of humans and parasites facilitates continued reintroduction outside of ongoing surveillance activities, which is critical to address for future malaria control and elimination efforts. Ongoing P. vivax research gaps in Peru include the following: identification of asymptomatic parasitemics, quantification of the contribution of patent and subpatent parasitemics to mosquito transmission, diagnosis of nonparasitemic hypnozoite carriers, and implementation of surveillance for potential emergence of chloroquine- and 8-aminoquinoline-resistant P. vivax. Clinical trials of tafenoquine in Peru have been promising, and glucose-6-phosphate dehydrogenase deficiency in the region has not been observed to be a limitation to its use. Larger-scale challenges for P. vivax (and malaria in general) in Peru include logistical difficulties in accessing remote riverine populations, consequences of government policy and poverty trends, and obtaining international funding for malaria control and elimination. PMID:27799639
Full Text Available BACKGROUND: Malaria elimination requires successful nationwide control efforts. Detecting the spatiotemporal distribution and mapping high-risk areas are useful to effectively target pockets of malaria endemic regions for interventions. OBJECTIVE: The aim of the study was to identify patterns of malaria distribution by space and time in unstable malaria transmission areas in northwest Ethiopia. METHODS: Data were retrieved from the monthly reports stored in the district malaria offices for the period between 2003 and 2012. Eighteen districts in the highland and fringe malaria areas were included and geo-coded for the purpose of this study. The spatial data were created in ArcGIS10 for each district. The Poisson model was used by applying Kulldorff methods using the SaTScan™ software to analyze the purely temporal, spatial and space-time clusters of malaria at a district levels. RESULTS: The study revealed that malaria case distribution has spatial, temporal, and spatiotemporal heterogeneity in unstable transmission areas. Most likely spatial malaria clusters were detected at Dera, Fogera, Farta, Libokemkem and Misrak Este districts (LLR =197764.1, p<0.001. Significant spatiotemporal malaria clusters were detected at Dera, Fogera, Farta, Libokemkem and Misrak Este districts (LLR=197764.1, p<0.001 between 2003/1/1 and 2012/12/31. A temporal scan statistics identified two high risk periods from 2009/1/1 to 2010/12/31 (LLR=72490.5, p<0.001 and from 2003/1/1 to 2005/12/31 (LLR=26988.7, p<0.001. CONCLUSION: In unstable malaria transmission areas, detecting and considering the spatiotemporal heterogeneity would be useful to strengthen malaria control efforts and ultimately achieve elimination.
Jamilu Abdullahi Faruk; Gboye Olufemi Ogunrinde; Aisha Indo Mamman
Background. Asymptomatic malaria parasitaemia has been documented in donor blood in West Africa. However, donated blood is not routinely screened for malaria parasites (MPs). The present study therefore aimed to document the frequency of blood transfusion-induced donor-recipient malaria parasitaemia patterns, in children receiving blood transfusion in a tertiary health-centre. Methodology. A cross-sectional, observational study involving 140 children receiving blood transfusion was carried ou...
van Esbroeck Marjan
Full Text Available Abstract Background Palutop+4 (All. Diag, Strasbourg, France, a four-band malaria rapid diagnostic test (malaria RDT targeting the histidine-rich protein 2 (HRP-2, Plasmodium vivax-specific parasite lactate dehydrogenase (Pv-pLDH and pan Plasmodium-specific pLDH (pan-pLDH was evaluated in a non-endemic setting on stored whole blood samples from international travellers suspected of malaria. Methods Microscopy corrected by PCR was the reference method. Samples include those infected by Plasmodium falciparum (n = 323, Plasmodium vivax (n = 97, Plasmodium ovale (n = 73 and Plasmodium malariae (n = 25 and 95 malaria negative samples. Results The sensitivities for the diagnosis of P. falciparum, P. vivax, P. malariae and P. ovale were 85.1%, 66.0%, 32.0% and 5.5%. Sensitivities increased at higher parasite densities and reached 90.0% for P. falciparum >100/μl and 83.8% for P. vivax > 500/μl. Fourteen P. falciparum samples reacted with the Pv-pLDH line, one P. vivax sample with the HRP-2 line, and respectively two and four P. ovale and P. malariae samples reacted with the HRP-2 line. Two negative samples gave a signal with the HRP-2 line. Faint and weak line intensities were observed for 129/289 (44.6% HRP-2 lines in P. falciparum samples, for 50/64 (78.1% Pv-pLDH lines in P. vivax samples and for 9/13 (69.2% pan-pLDH lines in P. ovale and P. malariae samples combined. Inter-observer reliabilities for positive and negative readings were excellent for the HRP-2 and Pv-pLDH lines (overall agreement > 92.0% and kappa-values for each pair of readers ≥ 0.88, and good for the pan-pLDH line (85.5% overall agreement and kappa-values ≥ 0.74. Conclusions Palutop+4 performed moderately for the detection of P. falciparum and P. vivax, but sensitivities were lower than those of three-band malaria RDTs.
Askling Helena H
Full Text Available Abstract In this position paper, the European Society for Clinical Microbiology and Infectious Diseases, Study Group on Clinical Parasitology, summarizes main issues regarding the management of imported malaria cases. Malaria is a rare diagnosis in Europe, but it is a medical emergency. A travel history is the key to suspecting malaria and is mandatory in patients with fever. There are no specific clinical signs or symptoms of malaria although fever is seen in almost all non-immune patients. Migrants from malaria endemic areas may have few symptoms. Malaria diagnostics should be performed immediately on suspicion of malaria and the gold- standard is microscopy of Giemsa-stained thick and thin blood films. A Rapid Diagnostic Test (RDT may be used as an initial screening tool, but does not replace urgent microscopy which should be done in parallel. Delays in microscopy, however, should not lead to delayed initiation of appropriate treatment. Patients diagnosed with malaria should usually be hospitalized. If outpatient management is preferred, as is the practice in some European centres, patients must usually be followed closely (at least daily until clinical and parasitological cure. Treatment of uncomplicated Plasmodium falciparum malaria is either with oral artemisinin combination therapy (ACT or with the combination atovaquone/proguanil. Two forms of ACT are available in Europe: artemether/lumefantrine and dihydroartemisinin/piperaquine. ACT is also effective against Plasmodium vivax, Plasmodium ovale, Plasmodium malariae and Plasmodium knowlesi, but these species can be treated with chloroquine. Treatment of persistent liver forms in P. vivax and P. ovale with primaquine is indicated after excluding glucose 6 phosphate dehydrogenase deficiency. There are modified schedules and drug options for the treatment of malaria in special patient groups, such as children and pregnant women. The potential for drug interactions and the role of food in the
Jensen, Anja T R; Magistrado, Pamela; Sharp, Sarah
Parasite-encoded variant surface antigens (VSAs) like the var gene-encoded Plasmodium falciparum erythrocyte membrane protein 1 (PfEMP1) family are responsible for antigenic variation and infected red blood cell (RBC) cytoadhesion in P. falciparum malaria. Parasites causing severe malaria in noni...... genes, such as PFD1235w/MAL7P1.1, appear to be involved in the pathogenesis of severe disease and are thus attractive candidates for a vaccine against life-threatening P. falciparum malaria....
Afrane, Yaw A; Zhou, Guofa; Githeko, Andrew K; Yan, Guiyun
In African highland areas where endemicity of malaria varies greatly according to altitude and topography, parasitaemia accompanied by fever may not be sufficient to define an episode of clinical malaria in endemic areas. To evaluate the effectiveness of malaria interventions, age-specific case definitions of clinical malaria needs to be determined. Cases of clinical malaria through active case surveillance were quantified in a highland area in Kenya and defined clinical malaria for different age groups. A cohort of over 1,800 participants from all age groups was selected randomly from over 350 houses in 10 villages stratified by topography and followed for two-and-a-half years. Participants were visited every two weeks and screened for clinical malaria, defined as an individual with malaria-related symptoms (fever [axillary temperature≥37.5°C], chills, severe malaise, headache or vomiting) at the time of examination or 1-2 days prior to the examination in the presence of a Plasmodium falciparum positive blood smear. Individuals in the same cohort were screened for asymptomatic malaria infection during the low and high malaria transmission seasons. Parasite densities and temperature were used to define clinical malaria by age in the population. The proportion of fevers attributable to malaria was calculated using logistic regression models. Incidence of clinical malaria was highest in valley bottom population (5.0% cases per 1,000 population per year) compared to mid-hill (2.2% cases per 1,000 population per year) and up-hill (1.1% cases per 1,000 population per year) populations. The optimum cut-off parasite densities through the determination of the sensitivity and specificity showed that in children less than five years of age, 500 parasites per μl of blood could be used to define the malaria attributable fever cases for this age group. In children between the ages of 5-14, a parasite density of 1,000 parasites per μl of blood could be used to define the
Philippa K Harris
Full Text Available Proteolytic shedding of surface proteins during invasion by apicomplexan parasites is a widespread phenomenon, thought to represent a mechanism by which the parasites disengage adhesin-receptor complexes in order to gain entry into their host cell. Erythrocyte invasion by merozoites of the malaria parasite Plasmodium falciparum requires the shedding of ectodomain components of two essential surface proteins, called MSP1 and AMA1. Both are released by the same merozoite surface "sheddase," but the molecular identity and mode of action of this protease is unknown. Here we identify it as PfSUB2, an integral membrane subtilisin-like protease (subtilase. We show that PfSUB2 is stored in apical secretory organelles called micronemes. Upon merozoite release it is secreted onto the parasite surface and translocates to its posterior pole in an actin-dependent manner, a trafficking pattern predicted of the sheddase. Subtilase propeptides are usually selective inhibitors of their cognate protease, and the PfSUB2 propeptide is no exception; we show that recombinant PfSUB2 propeptide binds specifically to mature parasite-derived PfSUB2 and is a potent, selective inhibitor of MSP1 and AMA1 shedding, directly establishing PfSUB2 as the sheddase. PfSUB2 is a new potential target for drugs designed to prevent erythrocyte invasion by the malaria parasite.
Griffing, Sean M; Gamboa, Dionicia; Udhayakumar, Venkatachalam
Malaria has been part of Peruvian life since at least the 1500s. While Peru gave the world quinine, one of the first treatments for malaria, its history is pockmarked with endemic malaria and occasional epidemics. In this review, major increases in Peruvian malaria incidence over the past hundred years are described, as well as the human factors that have facilitated these events, and concerted private and governmental efforts to control malaria. Political support for malaria control has varied and unexpected events like vector and parasite resistance have adversely impacted morbidity and mortality. Though the ready availability of novel insecticides like DDT and efficacious medications reduced malaria to very low levels for a decade after the post eradication era, malaria reemerged as an important modern day challenge to Peruvian public health. Its reemergence sparked collaboration between domestic and international partners towards the elimination of malaria in Peru.
Rodrigues, Amabelia; Schellenberg, Joanna Armstrong; Kofoed, Poul-Erik
OBJECTIVE: To describe the epidemiology of malaria in Guinea-Bissau, in view of the fact that more funds are available now for malaria control in the country. METHODS: From May 2003 to May 2004, surveillance for malaria was conducted among children less than 5 years of age at three health centres...... covering the study area of the Bandim Health Project (BHP) and at the outpatient clinic of the national hospital in Bissau. Cross-sectional surveys were conducted in the community in different malaria seasons. RESULTS: Malaria was overdiagnosed in both health centres and hospital. Sixty-four per cent...... of the children who presented at a health centre were clinically diagnosed with malaria, but only 13% of outpatient children who tested for malaria had malaria parasitaemia. Only 44% (963/2193) of children admitted to hospital with a diagnosis of malaria had parasitaemia. The proportion of positive cases...
Lilburn Timothy G
Full Text Available Abstract Background Malaria continues to be one of the most severe global infectious diseases, responsible for 1-2 million deaths yearly. The rapid evolution and spread of drug resistance in parasites has led to an urgent need for the development of novel antimalarial targets. Proteases are a group of enzymes that play essential roles in parasite growth and invasion. The possibility of designing specific inhibitors for proteases makes them promising drug targets. Previously, combining a comparative genomics approach and a machine learning approach, we identified the complement of proteases (degradome in the malaria parasite Plasmodium falciparum and its sibling species 123, providing a catalog of targets for functional characterization and rational inhibitor design. Network analysis represents another route to revealing the role of proteins in the biology of parasites and we use this approach here to expand our understanding of the systems involving the proteases of P. falciparum. Results We investigated the roles of proteases in the parasite life cycle by constructing a network using protein-protein association data from the STRING database 4, and analyzing these data, in conjunction with the data from protein-protein interaction assays using the yeast 2-hybrid (Y2H system 5, blood stage microarray experiments 678, proteomics 9101112, literature text mining, and sequence homology analysis. Seventy-seven (77 out of 124 predicted proteases were associated with at least one other protein, constituting 2,431 protein-protein interactions (PPIs. These proteases appear to play diverse roles in metabolism, cell cycle regulation, invasion and infection. Their degrees of connectivity (i.e., connections to other proteins, range from one to 143. The largest protease-associated sub-network is the ubiquitin-proteasome system which is crucial for protein recycling and stress response. Proteases are also implicated in heat shock response, signal peptide
Jun 1, 2015 ... Bayero Journal of Pure and Applied Sciences, 8(1): 80 – 83. Received: April ... INFECTED SUBJECTS IN USMANU DANFODIYO UNIVERSITY TEACHING. HOSPITAL ... genus contains over 125 species that cause malaria.
Jency Maria Koshy
Full Text Available Malaria is one of the most common parasitic infections in the developing countries. In Rural India, most patients would be treated by primary and secondary care physicians. This article is aimed at providing a feasible approach to the cases of malaria in mission hospitals and other rural hospitals taking into account all the resource limitations. A study done over one year on patients detected to have malaria at Jiwan Jyoti Christian Hospital in Sonbhadra district has helped the authors to identify the various challenges faced by doctors working in the rural hospitals. The article has looked at the various complications associated with malaria and their management. It has also stressed upon the increasing incidence of chloroquine resistance.
2011 - 2014 of the National Department of Health (NDoH) lists key objectives in achieving malaria .... message' through industrial theatre or comedy shows for schools, workplaces with the ... Health Care Re-engineering. Pretoria: NDoH, 2011.
van Thien, H.; Ackermans, M. T.; Weverling, G. J.; Dang Vinh, T.; Endert, E.; Kager, P. A.; Sauerwein, H. P.
BACKGROUND: In healthy subjects after an overnight fast, glucose production is for approximately 50% derived from glycogenolysis. If the fast is prolonged, glucose production decreases due to a decline in glycogenolysis, while gluconeogenesis remains stable. In cerebral malaria, glucose production
U.S. Department of Health & Human Services — NNDSS - Table II. Legionellosis to Malaria - 2017. In this Table, provisional cases of selected notifiable diseases (≥1,000 cases reported during the preceding...
U.S. Department of Health & Human Services — NNDSS - Table II. Legionellosis to Malaria - 2018. In this Table, provisional cases of selected notifiable diseases (≥1,000 cases reported during the preceding...
McKenzie, F. E; Prudhomme, Wendy A; Magill, Alan J; Forney, J. R; Permpanich, Barnyen; Lucas, Carmen; Gasser, Jr., Robert A; Wongsrichanalai, Chansuda
White blood cells (WBCs) were counted in 4697 individuals who presented to outpatient malaria clinics in Maesod, Tak Province, Thailand, and Iquitos, Peru, between 28 May and 28 August 1998 and between 17 May and 9 July 1999...
Dec 9, 2010 ... James Sang of the Kenyan government's Malaria Control Unit says the disease hits ... During the 1998 epidemic, almost four times more school-aged children caught ... This gave birth to the current phase of the project.
Community Involvement and Preception towards Malaria Prevention and Control Strategies in Rural Areas of Kersa District in Jimma Zone, Southwest Ethiopia. Wondimu Tesgera, Makonnen Aseffa, Bishaw Deboch, Wondwossen Kassahun ...
Ruth D Ellis
Full Text Available A Phase 1 dose escalating study was conducted in malaria naïve adults to assess the safety, reactogenicity, and immunogenicity of the blood stage malaria vaccine BSAM2/Alhydrogel®+ CPG 7909. BSAM2 is a combination of the FVO and 3D7 alleles of recombinant AMA1 and MSP1(42, with equal amounts by weight of each of the four proteins mixed, bound to Alhydrogel®, and administered with the adjuvant CPG 7909. Thirty (30 volunteers were enrolled in two dose groups, with 15 volunteers receiving up to three doses of 40 µg total protein at Days 0, 56, and 180, and 15 volunteers receiving up to three doses of 160 µg protein on the same schedule. Most related adverse events were mild or moderate, but 4 volunteers experienced severe systemic reactions and two were withdrawn from vaccinations due to adverse events. Geometric mean antibody levels after two vaccinations with the high dose formulation were 136 µg/ml for AMA1 and 78 µg/ml for MSP1(42. Antibody responses were not significantly different in the high dose versus low dose groups and did not further increase after third vaccination. In vitro growth inhibition was demonstrated and was closely correlated with anti-AMA1 antibody responses. A Phase 1b trial in malaria-exposed adults is being conducted.Clinicaltrials.gov NCT00889616.
Kuesap, Jiraporn; Chaijaroenkul, W.; Rungsihirunrat, K.; Pongjantharasatien, K.; Na-Bangchang, Kesara
Hemoglobinopathy and malaria are commonly found worldwide particularly in malaria endemic areas. Thalassemia, the alteration of globin chain synthesis, has been reported to confer resistance against malaria. The prevalence of thalassemia was investigated in 101 malaria patients with Plasmodium falciparum and Plasmodium vivax along the Thai-Myanmar border to examine protective effect of thalassemia against severe malaria. Hemoglobin typing was performed using low pressure liquid chromatography (LPLC) and α-thalassemia was confirmed by multiplex PCR. Five types of thalassemia were observed in malaria patients. The 2 major types of thalassemia were Hb E (18.8%) and α-thalassemia-2 (11.9%). There was no association between thalassemia hemoglobinopathy and malaria parasitemia, an indicator of malaria disease severity. Thalassemia had no significant association with P. vivax infection, but the parasitemia in patients with coexistence of P. vivax and thalassemia was about 2-3 times lower than those with coexistence of P. falciparum and thalassemia and malaria without thalassemia. Furthermore, the parasitemia of P. vivax in patients with coexistence of Hb E showed lower value than coexistence with other types of thalassemia and malaria without coexistence. Parasitemia, hemoglobin, and hematocrit values in patients with coexistence of thalassemia other than Hb E were significantly lower than those without coexistence of thalassemia. Furthermore, parasitemia with coexistence of Hb E were 2 times lower than those with coexistence of thalassemia other than Hb E. In conclusion, the results may, at least in part, support the protective effect of thalassemia on the development of hyperparasitemia and severe anemia in malaria patients. PMID:26174819
Full Text Available Abstract Background Rapid urbanization in sub-Saharan Africa has a major impact on malaria epidemiology. While much is known about malaria in rural areas in Burkina Faso, the urban situation is less well understood. Methods An assessment of urban malaria was carried out in Ouagadougou in November -December, 2002 during which a rapid urban malaria appraisal (RUMA was applied. Results The school parasitaemia prevalence was relatively high (48.3% at the cold and dry season 2002. Routine malaria statistics indicated that seasonality of malaria transmission was marked. In the health facilities, the number of clinical cases diminished quickly at the start of the cold and dry season and the prevalence of parasitaemia detected in febrile and non-febrile cases was 21.1% and 22.0%, respectively. The health facilities were likely to overestimate the malaria incidence and the age-specific fractions of malaria-attributable fevers were low (0–0.13. Peak prevalence tended to occur in older children (aged 6–15 years. Mapping of Anopheles sp. breeding sites indicated a gradient of endemicity between the urban centre and the periphery of Ouagadougou. A remarkable link was found between urban agriculture activities, seasonal availability of water supply and the occurrence of malaria infections in this semi-arid area. The study also demonstrated that the usage of insecticide-treated nets and the education level of family caretakers played a key role in reducing malaria infection rates. Conclusion These findings show that determining local endemicity and the rate of clinical malaria cases are urgently required in order to target control activities and avoid over-treatment with antimalarials. The case management needs to be tailored to the level of the prevailing endemicity.
Kumar, Ashwani; Chery, Laura; Biswas, Chinmoy; Dubhashi, Nagesh; Dutta, Prafulla; Dua, Virendra Kumar; Kacchap, Mridula; Kakati, Sanjeeb; Khandeparkar, Anar; Kour, Dalip; Mahajanj, Satish N.; Maji, Ardhendu; Majumder, Partha; Mohanta, Jagadish; Mohapatra, Pradyumna K.; Narayanasamy, Krishnamoorthy; Roy, Krishnangshu; Shastri, Jayanthi; Valecha, Neena; Vikash, Rana; Wani, Reena; White, John; Rathod, Pradipsinh K
The “Malaria Evolution in South Asia” (MESA) program project is an International Center of Excellence for Malaria Research (ICEMR) sponsored by the US National Institutes of Health. This US–India collaborative program will study the origin of genetic diversity of malaria parasites and their selection on the Indian subcontinent. This knowledge should contribute to a better understanding of unexpected disease outbreaks and unpredictable disease presentations from Plasmodium falciparum and Plasmodium vivax infections. In this first of two reviews, we highlight malaria prevalence in India. In particular, we draw attention to variations in distribution of different human-parasites and different vectors, variation in drug resistance traits, and multiple forms of clinical presentations. Uneven malaria severity in India is often attributed to large discrepancies in health care accessibility as well as human migrations within the country and across neighboring borders. Poor access to health care goes hand in hand with poor reporting from some of the same areas, combining to possibly distort disease prevalence and death from malaria in some parts of India. Corrections are underway in the form of increased resources for disease control, greater engagement of village-level health workers for early diagnosis and treatment, and possibly new public–private partnerships activities accompanying traditional national malaria control programs in the most severely affected areas. A second accompanying review raises the possibility that, beyond uneven health care, evolutionary pressures may alter malaria parasites in ways that contribute to severe disease in India, particularly in the NE corridor of India bordering Myanmar Narayanasamy et al., 2012. PMID:22248528
Oria, Prisca A.
Chapter 1 presents the background information relevant to the subject matter and methods of this thesis. These include the application of social and behavioural sciences in malaria control, the SolarMal project and malaria in Kenya. It also presents the research objective, question and design that informed this thesis. Chapter 2 systematically documented and analysed how the mosquito trapping technology and related social contexts mutually shaped each other and how this mutual shaping impacte...
Full Text Available A recently proposed mechanism of protection for haemoglobin C (HbC; beta6Glu-->Lys links an abnormal display of PfEMP1, an antigen involved in malaria pathogenesis, on the surface of HbC infected erythrocytes together with the observation of reduced cytoadhesion of parasitized erythrocytes and impaired rosetting in vitro. We investigated the impact of this hypothesis on the development of acquired immunity against Plasmodium falciparum variant surface antigens (VSA encoding PfEMP1 in HbC in comparison with HbA and HbS carriers of Burkina Faso. We measured: i total IgG against a single VSA, A4U, and against a panel of VSA from severe malaria cases in human sera from urban and rural areas of Burkina Faso of different haemoglobin genotypes (CC, AC, AS, SC, SS; ii total IgG against recombinant proteins of P. falciparum asexual sporozoite, blood stage antigens, and parasite schizont extract; iii total IgG against tetanus toxoid. Results showed that the reported abnormal cell-surface display of PfEMP1 on HbC infected erythrocytes observed in vitro is not associated to lower anti- PfEMP1 response in vivo. Higher immune response against the VSA panel and malaria antigens were observed in all adaptive genotypes containing at least one allelic variant HbC or HbS in the low transmission urban area whereas no differences were detected in the high transmission rural area. In both contexts the response against tetanus toxoid was not influenced by the beta-globin genotype. These findings suggest that both HbC and HbS affect the early development of naturally acquired immunity against malaria. The enhanced immune reactivity in both HbC and HbS carriers supports the hypothesis that the protection against malaria of these adaptive genotypes might be at least partially mediated by acquired immunity against malaria.
Lyke, Kirsten E
Great progress has been made in reducing malaria morbidity and mortality, yet the parasite continues to cause a startling 200 million infections and 500 000 deaths annually. Malaria vaccine development is pushing new boundaries by steady advancement toward a licensed product. Despite 50 years of research, the complexity of Plasmoidum falciparum confounds all attempts to eradicate the organism. This very complexity has pushed the boundaries of vaccine development to new heights, yet it remains to be seen if an affordable vaccine can provide durable and high-level protection. Novel vaccines such as RTS,S/AS01E are on the edge of licensure, but old techniques have resurged with the ability to deliver vialed, whole organism vaccines. Novel adjuvants, multistage/multiantigen approaches and transmission blocking vaccines all contribute to a multipronged battle plan to conquer malaria. Vaccines are the most cost-effective tools to control infectious diseases, yet the complexity of malaria has frustrated all attempts to develop an effective product. This review concentrates on recent advances in malaria vaccine development that lend hope that a vaccine can be produced and malaria eradicated.
Michelle N Wykes
Full Text Available Malaria is a significant global burden but after >30 years of effort there is no vaccine on the market. While the complex life cycle of the parasite presents several challenges, many years of research have also identified several mechanisms of immune evasion by Plasmodium spp.. Recent research on malaria, has investigated the Programmed cell death-1 (PD-1 pathway which mediates exhaustion of T cells, characterized by poor effector functions and recall responses and in some cases loss of the cells by apoptosis. Such studies have shown exhaustion of CD4+ T cells and an unappreciated role for CD8+ T cells in promoting sterile immunity against blood stage malaria. This is because PD-1 mediates up to a 95% reduction in numbers and functional capacity of parasite-specific CD8+ T cells, thus masking their role in protection. The role of T cell exhaustion during malaria provides an explanation for the absence of sterile immunity following the clearance of acute disease which will be relevant to future malaria-vaccine design and suggests the need for novel therapeutic solutions. This review will thus examine the role of PD-1-mediated T cell exhaustion in preventing lasting immunity against malaria.
Robert H. Zimmerman
Full Text Available The author reviews the malaria research program in Sucre State, Venezuela, taking an ecosystem approach. The goal was to determine which methods could have been introduced at the onset that would have made the study more ecological and interdisciplinary. Neither an ecosystem approach nor integrated disease control were in place at the time of the study. This study began to introduce an ecosystem approach when two contrasting ecosystems in Sucre State were selected for study and vector control methods were implemented based on research results. The need to have a health policy in place with an eco-health approach is crucial to the success of research and control. The review suggests that sustainability is low when not all the stakeholders are involved in the design and implementation of the research and control strategy development. The lack of community involvement makes sustainability doubtful. The author concludes that there were two interdependent challenges for malaria control: development of an ecosystem approach for malaria research and control, and the implementation of an integrated disease control strategy, with malaria as one of the important health issues.O autor faz uma revisão do programa de pesquisa sobre malária no Estado de Sucre, Venezuela, à luz de uma abordagem ecossistêmica. O objetivo era determinar quais métodos poderiam ter sido introduzidos no início do estudo para torná-lo mais ecológico e interdisciplinar. A fase inicial do estudo não incluía uma abordagem ecossistêmica ou controle integrado da doença, que só foram incorporados quando dois ecossistemas contrastantes no Estado de Sucre foram selecionados para pesquisa, junto com um método de controle de vetores com base nos resultados. Uma política de saúde bem-definida com uma abordagem ecossistêmica é crucial para o sucesso de uma estratégia de pesquisa e controle. Esta revisão sugere que a sustentabilidade é baixa se todos os atores não estiverem
Martin, Carrin; Curtis, Bronwyn; Fraser, Colleen; Sharp, Brian
The paper aims to outline the innovative development and application of a Geographical Information System based Malaria Information System for malaria research and control in South Africa. This system is a product of collaboration between the Malaria Control Programmes and the Malaria Research Programme of the Medical Research Council of South Africa. The ability of such a system to process data timeously into a usable format is discussed, as well as its relevance to malaria research, appropriate malaria control measures, tourism, and social and economic development.
Malaria causes an estimated 225 million cases and 781,000 deaths every year. About 85% of the deaths are in children under five years of age. Malaria is caused by the Plasmodium parasite which is transmitted by the Anopheles mosquito vector. Mainly two methods of intervention are used for
Quispe, Antonio M; Pozo, Edwar; Guerrero, Edith; Durand, Salomón; Baldeviano, G Christian; Edgel, Kimberly A; Graf, Paul C F; Lescano, Andres G
Severe malaria caused by Plasmodium vivax is no longer considered rare. To describe its clinical features, we performed a retrospective case control study in the subregion of Luciano Castillo Colonna, Piura, Peru, an area with nearly exclusive vivax malaria transmission. Severe cases and the subset of critically ill cases were compared with a random set of uncomplicated malaria cases (1:4). Between 2008 and 2009, 6,502 malaria cases were reported, including 106 hospitalized cases, 81 of which fit the World Health Organization definition for severe malaria. Of these 81 individuals, 28 individuals were critically ill (0.4%, 95% confidence interval = 0.2-0.6%) with severe anemia (57%), shock (25%), lung injury (21%), acute renal failure (14%), or cerebral malaria (11%). Two potentially malaria-related deaths occurred. Compared with uncomplicated cases, individuals critically ill were older (38 versus 26 years old, P < 0.001), but similar in other regards. Severe vivax malaria monoinfection with critical illness is more common than previously thought. © The American Society of Tropical Medicine and Hygiene.
Greenwood, Brian; Bhasin, Amit; Targett, Geoffrey
Recently, there has been a major increase in financial support for malaria control. Most of these funds have, appropriately, been spent on the tools needed for effective prevention and treatment of malaria such as insecticide-treated bed nets, indoor residual spraying and artemisinin combination therapy. There has been less investment in the training of the scientists from malaria-endemic countries needed to support these large and increasingly complex malaria control programmes, especially in Africa. In 2000, with support from the Bill & Melinda Gates Foundation, the Gates Malaria Partnership was established to support postgraduate training of African scientists wishing to pursue a career in malaria research. The programme had three research capacity development components: a PhD fellowship programme, a postdoctoral fellowship programme and a laboratory infrastructure programme. During an 8-year period, 36 African PhD students and six postdoctoral fellows were supported, and two research laboratories were built in Tanzania. Some of the lessons learnt during this project--such as the need to improve PhD supervision in African universities and to provide better support for postdoctoral fellows--are now being applied to a successor malaria research capacity development programme, the Malaria Capacity Development Consortium, and may be of interest to other groups involved in improving postgraduate training in health sciences in African universities. © 2012 Blackwell Publishing Ltd.
Full Text Available INTRODUCTION: Malaria is re-emerging in most of the African highlands exposing the non immune population to deadly epidemics. A better understanding of the factors impacting transmission in the highlands is crucial to improve well targeted malaria control strategies. METHODS AND FINDINGS: A conceptual model of potential malaria risk factors in the highlands was built based on the available literature. Furthermore, the relative importance of these factors on malaria can be estimated through "classification and regression trees", an unexploited statistical method in the malaria field. This CART method was used to analyse the malaria risk factors in the Burundi highlands. The results showed that Anopheles density was the best predictor for high malaria prevalence. Then lower rainfall, no vector control, higher minimum temperature and houses near breeding sites were associated by order of importance to higher Anopheles density. CONCLUSIONS: In Burundi highlands monitoring Anopheles densities when rainfall is low may be able to predict epidemics. The conceptual model combined with the CART analysis is a decision support tool that could provide an important contribution toward the prevention and control of malaria by identifying major risk factors.
Protopopoff, Natacha; Van Bortel, Wim; Speybroeck, Niko; Van Geertruyden, Jean-Pierre; Baza, Dismas; D'Alessandro, Umberto; Coosemans, Marc
Malaria is re-emerging in most of the African highlands exposing the non immune population to deadly epidemics. A better understanding of the factors impacting transmission in the highlands is crucial to improve well targeted malaria control strategies. A conceptual model of potential malaria risk factors in the highlands was built based on the available literature. Furthermore, the relative importance of these factors on malaria can be estimated through "classification and regression trees", an unexploited statistical method in the malaria field. This CART method was used to analyse the malaria risk factors in the Burundi highlands. The results showed that Anopheles density was the best predictor for high malaria prevalence. Then lower rainfall, no vector control, higher minimum temperature and houses near breeding sites were associated by order of importance to higher Anopheles density. In Burundi highlands monitoring Anopheles densities when rainfall is low may be able to predict epidemics. The conceptual model combined with the CART analysis is a decision support tool that could provide an important contribution toward the prevention and control of malaria by identifying major risk factors.
Faruk, Jamilu Abdullahi; Ogunrinde, Gboye Olufemi; Mamman, Aisha Indo
Asymptomatic malaria parasitaemia has been documented in donor blood in West Africa. However, donated blood is not routinely screened for malaria parasites (MPs). The present study therefore aimed to document the frequency of blood transfusion-induced donor-recipient malaria parasitaemia patterns, in children receiving blood transfusion in a tertiary health-centre. A cross-sectional, observational study involving 140 children receiving blood transfusion was carried out. Blood donor units and patients' blood samples were obtained, for the determination of malaria parasites (MPs). Giemsa staining technique was used to determine the presence of malaria parasitaemia. Malaria parasites were detected in 7% of donor blood and in 8.3% of the recipients' pretransfusion blood. The incidence of posttransfusion MPs was 3%, but none of these were consistent with blood transfusion-induced malaria, as no child with posttransfusion parasitaemia was transfused with parasitized donor blood. Majority of the blood transfusions (89.4%) had no MPs in either donors or recipients, while 6.8% had MPs in both donors and recipients, with the remaining 3.8% showing MPs in recipients alone. In conclusion, the incidence of posttransfusion malaria parasitaemia appears low under the prevailing circumstances.
Amari-Omaka, Lois Nnenna; Obande-Ogbuinya, Nkiru Edith
The purpose of this study was to determine sources of malaria information among pregnant women in Ebonyi state and implications for malaria education. The cross sectional research design was adopted and stratified sampling technique was used to select a total of five hundred and four (504) pregnant women from 12 hospitals in the state. A self…
Full Text Available Salivary gland proteins of Anopheles mosquitoes offer attractive targets to understand interactions with sporozoites, blood feeding behavior, homeostasis, and immunological evaluation of malaria vectors and parasite interactions. To date limited studies have been carried out to elucidate salivary proteins of An. stephensi salivary glands. The aim of the present study was to provide detailed analytical attributives of functional salivary gland proteins of urban malaria vector An. stephensi. A proteomic approach combining one-dimensional electrophoresis (1DE, ion trap liquid chromatography mass spectrometry (LC/MS/MS, and computational bioinformatic analysis was adopted to provide the first direct insight into identification and functional characterization of known salivary proteins and novel salivary proteins of An. stephensi. Computational studies by online servers, namely, MASCOT and OMSSA algorithms, identified a total of 36 known salivary proteins and 123 novel proteins analysed by LC/MS/MS. This first report describes a baseline proteomic catalogue of 159 salivary proteins belonging to various categories of signal transduction, regulation of blood coagulation cascade, and various immune and energy pathways of An. stephensi sialotranscriptome by mass spectrometry. Our results may serve as basis to provide a putative functional role of proteins in concept of blood feeding, biting behavior, and other aspects of vector-parasite host interactions for parasite development in anopheline mosquitoes.
Alam, Mohammad Shafiul; Kabir, Mohammad Moktadir; Hossain, Mohammad Sharif; Naher, Shamsun; Ferdous, Nur E Naznin; Khan, Wasif Ali; Mondal, Dinesh; Karim, Jahirul; Shamsuzzaman, A K M; Ahmed, Be-Nazir; Islam, Akramul; Haque, Rashidul
Malaria is endemic in 13 districts of Bangladesh. A baseline malaria prevalence survey across the endemic districts of Bangladesh was conducted in 2007, when the prevalence was reported around 39.7 per 1000 population. After two rounds of Global Fund to Fight AIDS, Tuberculosis and Malaria (GFATM)-funded intervention by the National Malaria Control Programme (NMCP) and a BRAC-led NGO consortium, a follow-up survey was conducted across the malaria-endemic districts of Bangladesh to measure the change in prevalence rate and in people's knowledge of malaria. The survey was carried out from August to November 2013 in 70 upazilas (sub-districts) of 13 malaria-endemic districts of Bangladesh, following the same multi-stage cluster sampling design and the same number of households enrolled during the baseline prevalence survey in 2007, to collect 9750 randomly selected blood samples. For on-the-spot diagnosis of malaria, a rapid diagnostic test was used. The household head or eldest person available was interviewed using a pre-coded structured questionnaire to collect data on the knowledge and awareness of malaria in the household. Based on a weighted calculation, the overall malaria prevalence was found to be 1.41 per 1000 population. The proportion of Plasmodium falciparum mono-infection was 77.78% while both Plasmodium vivax mono-infection and mixed infection of the two species were found to be 11.11%. Bandarban had the highest prevalence (6.67 per 1000 population). Knowledge of malaria signs, symptoms and mode of transmission were higher in the follow-up survey (97.26%) than the baseline survey. Use of bed nets for prevention of malaria was found to be high (90.15%) at respondent level. People's knowledge of selected parameters increased significantly during the follow-up survey compared to the baseline survey conducted in 2007. A reduced prevalence rate of malaria and increased level of knowledge were observed in the present malaria prevalence survey in Bangladesh.
Eckart, W U; Vondra, H
The epidemiological and pharmacological fight against malaria and German malaria research during the Nazi dictatorship were completely under the spell of war. The Oberkommando des Heeres (German supreme command of the army) suffered the bitter experience of unexpected high losses caused by malaria especially at the Greek front (Metaxes line) but also in southern Russia and in the Ukraine. Hastily raised anti-malaria units tried to teach soldiers how to use the synthetic malaria drugs (Plasmochine, Atebrine) properly. Overdoses of these drugs were numerous during the first half of the war whereas in the second half it soon became clear that it would not be possible to support the army due to insufficient quantities of plasmochine and atebrine. During both running fights and troop withdrawals at all southern and southeastern fronts there was hardly any malaria prophylaxis or treatment. After war and captivity many soldiers returned home to endure heavy malaria attacks. In German industrial (Bayer, IG-Farben) and military malaria laboratories of the Heeres-Sanitäts-Akademie (Army Medical Academy) the situation was characterised by a hasty search for proper dosages of anti-malaria drugs, adequate mechanical and chemical prophylaxis (Petroleum, DDT, and other insecticides) as well as an anti-malaria vaccine. Most importantly, large scale research for proper atebrine and plasmochine dosages was conducted in German concentration camps and mental homes. In Dachau Professor Claus Schilling tested synthetic malaria drugs and injected helpless prisoners with high and sometimes lethal doses. Since the 1920s he had been furiously looking for an anti-malaria vaccine in Italian mental homes and from 1939 he continued his experiments in Dachau. Similar experiments were also performed in Buchenwald and in a psychiatric clinic in Thuringia, where Professor Gerhard Rose tested malaria drugs with mentally ill Russian prisoners of war. Schilling was put to death for his criminal
Oner, Yaşar Ali; Okutan, Salih Erkan; Artinyan, Elizabeth; Kocazeybek, Bekir
Malaria is a parasitic infection caused by Plasmodium species and it is especially seen in tropical and subtropical areas. We aimed to evaluate the effects of the infection in Afghanistan, which is an endemic place for malaria and had severe socio-economical lost after the war. We also compared these data with the ones that were recorded before the war. Blood samples were taken from 376 malaria suspected patients who come to the health center, established by the medical group of Istanbul Medical Faculty in 2002, Afghanistan. Blood samples were screened using the OPTIMAL Rapid Malaria Test and Giemsa staining method. In 95 (25.3%) patients diagnosis was malaria. In 65 patients (17.3%) the agent of the infection was P. falciparum and in 30 patients (8%) agents were other Plasmodium species.
Wiese, Lothar; Bruun, Brita; Baek, Leif
Malaria may be misdiagnosed in non-endemic countries when the necessary experience for rapid expert microscopy is lacking. Rapid diagnostic tests may improve the diagnosis and may play a role as a bedside diagnostic tool. In a multicentre study we recruited patients suspected of malaria over...... a period of 14 months. The Binax Now Malaria rapid test was used at the bedside and in the clinical microbiology laboratory. The training of clinical staff was monitored and their experience with the use of the test was recorded. 542 patients were included, 80 of whom had malaria diagnosed by microscopy...... be useful for the diagnosis of P. falciparum malaria when used by routine laboratory staff, but could lead to misdiagnoses when used at the bedside. Microscopy is still essential in order to identify the few missed diagnoses, to determine the degree of parasitaemia, and to ensure species diagnosis...
Impoinvil Daniel E
Full Text Available Abstract Integrated vector management (IVM is defined as "a rational decision-making process for the optimal use of resources for vector control" and includes five key elements: 1 evidence-based decision-making, 2 integrated approaches 3, collaboration within the health sector and with other sectors, 4 advocacy, social mobilization, and legislation, and 5 capacity-building. In 2004, the WHO adopted IVM globally for the control of all vector-borne diseases. Important recent progress has been made in developing and promoting IVM for national malaria control programmes in Africa at a time when successful malaria control programmes are scaling-up with insecticide-treated nets (ITN and/or indoor residual spraying (IRS coverage. While interventions using only ITNs and/or IRS successfully reduce transmission intensity and the burden of malaria in many situations, it is not clear if these interventions alone will achieve those critical low levels that result in malaria elimination. Despite the successful employment of comprehensive integrated malaria control programmes, further strengthening of vector control components through IVM is relevant, especially during the "end-game" where control is successful and further efforts are required to go from low transmission situations to sustained local and country-wide malaria elimination. To meet this need and to ensure sustainability of control efforts, malaria control programmes should strengthen their capacity to use data for decision-making with respect to evaluation of current vector control programmes, employment of additional vector control tools in conjunction with ITN/IRS tactics, case-detection and treatment strategies, and determine how much and what types of vector control and interdisciplinary input are required to achieve malaria elimination. Similarly, on a global scale, there is a need for continued research to identify and evaluate new tools for vector control that can be integrated with
Tonkin-Hill, Gerry Q.; Trianty, Leily; Noviyanti, Rintis; Nguyen, Hanh H. T.; Sebayang, Boni F.; Lampah, Daniel A.; Marfurt, Jutta; Cobbold, Simon A.; Rambhatla, Janavi S.; McConville, Malcolm J.; Rogerson, Stephen J.; Brown, Graham V.; Day, Karen P.; Price, Ric N.; Anstey, Nicholas M.
Within the human host, the malaria parasite Plasmodium falciparum is exposed to multiple selection pressures. The host environment changes dramatically in severe malaria, but the extent to which the parasite responds to—or is selected by—this environment remains unclear. From previous studies, the parasites that cause severe malaria appear to increase expression of a restricted but poorly defined subset of the PfEMP1 variant, surface antigens. PfEMP1s are major targets of protective immunity. Here, we used RNA sequencing (RNAseq) to analyse gene expression in 44 parasite isolates that caused severe and uncomplicated malaria in Papuan patients. The transcriptomes of 19 parasite isolates associated with severe malaria indicated that these parasites had decreased glycolysis without activation of compensatory pathways; altered chromatin structure and probably transcriptional regulation through decreased histone methylation; reduced surface expression of PfEMP1; and down-regulated expression of multiple chaperone proteins. Our RNAseq also identified novel associations between disease severity and PfEMP1 transcripts, domains, and smaller sequence segments and also confirmed all previously reported associations between expressed PfEMP1 sequences and severe disease. These findings will inform efforts to identify vaccine targets for severe malaria and also indicate how parasites adapt to—or are selected by—the host environment in severe malaria. PMID:29529020
Full Text Available Malaria morbidity in Moru health center, with parameter Annual Parasite Incident (API, amounted to 16.9% in 2014. This figure was still high when compared to the target of eliminating malaria in Indonesia about <1% in 2030. Incidence of malaria is more common in children aged 5 months - <12 years. This high rates of malaria leads to poverty, low level of learning achievement of children and in pregnant women causing low birth weight in babies and death. The purpose of this study was to analyze the factors that influence the incidence of tertian and Tropikana malaria or combined Tropikana and tertian (mix in Moru PHC in sub-district Alor Southwestern, Alor Regency.This study used a cross-sectional design, the population of study were all patients undergoing peripheral blood examination in Moru PHC’s laboratory from June to October 2015. The number of samples in this study was 173 respondents. The sampling technique was Simple Random Sampling. Instruments of data collection were a questionnaire and observation sheet.Results of the study by Chi-Square test showed that the factors influencing the incidence of malaria were socioeconomic status (sig 0,000, education level (sig 0.001. By using multivariate analysis with logistic regression test, results were obtained the age of 5 months - <12 value (sig 0.025 and socioeconomic status (sig 0,000 influencing the incidence of malaria.Variables that affect the incidence of malaria were demographic factors such as age, education level, socioeconomic status. It is advisable to harness swamp thus improving the economic status of society and build permanent house. Keywords: incidence malaria, demographic factors, history of malaria
Full Text Available Abstract Background Highland areas of Africa are mostly malaria hypoendemic, due to climate which is not appropriate for anophelines development and their reproductive fitness. In view of designing a malaria control strategy in Western Cameroon highlands, baseline data on anopheline species bionomics were collected. Methods Longitudinal entomological surveys were conducted in three localities at different altitudinal levels. Mosquitoes were captured when landing on human volunteers and by pyrethrum spray catches. Sampled Anopheles were tested for the presence of Plasmodium circumsporozoite proteins and their blood meal origin with ELISA. Entomological parameters of malaria epidemiology were assessed using Mac Donald's formula. Results Anopheline species diversity and density decreased globally from lowland to highland. The most aggressive species along the altitudinal transect was Anopheles gambiae s.s. of S molecular form, followed in the lowland and on the plateau by An. funestus, but uphill by An. hancocki. An. gambiae and An. ziemanni exhibited similar seasonal biting patterns at the different levels, whereas different features were observed for An. funestus. Only indoor resting species could be captured uphill; it is therefore likely that endophilic behaviour is necessary for anophelines to climb above a certain threshold. Of the ten species collected along the transect, only An. gambiae and An. funestus were responsible for malaria transmission, with entomological inoculation rates (EIR of 90.5, 62.8 and zero infective bites/human/year in the lowland, on the plateau and uphill respectively. The duration of gonotrophic cycle was consistently one day shorter for An. gambiae as compared to An. funestus at equal altitude. Altitudinal climate variations had no effect on the survivorship and the subsequent life expectancy of the adult stage of these malaria vectors, but most probably on aquatic stages. On the contrary increasing altitude
profound influence on both malaria and pneumonia occurrence and are responsible directly for ... Key words: Malaria occurrence, change points, climate- disease, pneumonia. ..... formation of tall clouds and onset of rainy season, we observe ...
Aug 2, 2011 ... (2001) similarly found a relationship between level. *Corresponding author: Tel: +234 ..... Response of Students to Malaria and Therapy in a. University in ... Implementation of Pre-travel Advice. Good for. Malaria; Bad for ...
Scepticism towards insecticide treated mosquito nets for malaria control in rural ... especially among under-five year children and pregnant women in poor rural ... through social marketing strategy for malaria control prior to the introduction of ...
Leahy, T R
Imported childhood malaria has never been studied in Ireland. We aimed to document the incidence and species of malaria in children presenting to paediatric hospitals in Dublin and to examine management and outcome measures.
An increasing number of patients with severe complicated Plasmodium falciparum malaria are presenting to South African hospitals, having travelled through malariaendemic countries from Central and East Africa. This report concerns an immigrant from Pakistan who developed severe cerebral malaria.