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Query: UMLS:C0024530 (malaria)
 44,886 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Molecular processes that govern pathogenic features of erythrocyte invasion and cytoadherence in malaria are reliant on Plasmodium-specific Duffy-binding-like domains (DBLs). These cysteine-rich modules recognize diverse host cell-surface receptors during pathogenesis. DBLs of parasite erythrocyte-binding proteins mediate invasion, and those from the antigenically variant P. falciparum erythrocyte membrane protein 1 (PfEMP1) have been implicated in cytoadherence. The simian and human malarial parasites, P. knowlesi and P. vivax, invade human erythrocytes exclusively through the host DARC receptor (Duffy antigen receptor for chemokines). Here we present the crystal structure of the P. knowlesi DBL domain (Pkalpha-DBL), which binds to DARC during invasion of human erythrocytes. Pkalpha-DBL retains the overall fold observed in DBLs from P. falciparum erythrocyte-binding antigen (EBA)-175 (ref. 4). Mapping the residues that have previously been implicated in binding highlights a fairly flat but exposed site for DARC recognition in subdomain 2 of Pkalpha-DBL; this is in sharp contrast to receptor recognition by EBA-175 (ref. 4). In Pkalpha-DBL, the residues that contact DARC and the clusters of residues under immune pressure map to opposite surfaces of the DBL, and suggest a possible mechanism for immune evasion by P. vivax. Our comparative structural analysis of Pkalpha-DBL and P. falciparum EBA-175 provides a framework for the understanding of malaria parasite DBLs, and may affect the development of new prophylactic and therapeutic strategies.
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PMID:Structural basis for Duffy recognition by the malaria parasite Duffy-binding-like domain. 1687 18

Erythrocyte invasion by malaria parasites is a multi-step process requiring specific molecular interactions between merozoites and erythrocyte surface receptors. Human Duffy blood group protein is the receptor for Plasmodium vivax merozoite invasion to red blood cells. The cognate parasite ligand for Duffy protein is a 135 kDa Duffy binding protein (DBP). Previously, we defined the domain on the N-terminus of human Duffy protein required for DBP binding and showed that a 35-mer N-terminal peptide inhibited DBP binding to Duffy positive red cells in vitro. There is no efficient in vitro culture system or small animal model to study P. vivax ligand binding and invasion to red blood cells. Plasmodium yoelii is frequently used to study the interaction between host receptors and parasite ligands. Similar to human parasite P. vivax, rodent malaria parasite P. yoelii also uses Duffy protein on mouse RBCs for invasion. However, the domain on the mouse Duffy for P. yoelii binding is not known. In this communication, using a mouse model, we show that an antibody against the N-terminus of mouse Duffy protein inhibited P. yoelii invasion in the mouse. In addition, by using small peptides from the N-terminal exocellular domain, we defined the domain on the Duffy protein for P. yoelii binding and invasion to mouse erythrocytes. Our results also indicated that small peptides from the host receptor could act as decoy receptors and may be utilized as potential antimalarial drugs.
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PMID:The domain on the mouse Duffy protein for Plasmodium yoelii binding and invasion to mouse erythrocytes. 1638 20

Duffy-binding like (DBL) domains are common to two different families of malaria proteins that are involved in parasite invasion of erythrocytes or cytoadhesion of infected erythrocytes. DBL domain crystal structures have recently been solved for two different erythrocyte binding ligands, EBA-175 and the Plasmodium knowlesi alpha Duffy binding protein. These structures reveal different mechanisms for DBL binding and erythrocyte invasion. This review summarizes recent work on DBL domain binding and immune evasion and proposes a new structural model for how these domains adapted to intense antibody surveillance at the infected erythrocyte surface.
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PMID:Disguising itself--insights into Plasmodium falciparum binding and immune evasion from the DBL crystal structure. 1662 Oct 67

The interactions of Plasmodium falciparum infected erythrocytes parasitized red blood cells (pRBC) with endothelial receptors and erythrocytes are mediated by multiple Duffy-binding like (DBL) and cysteine-rich interdomain region (CIDR) domains harboured in the Plasmodium falciparum erythrocyte membrane protein 1 (PfEMP1). The success of a subunit vaccine based on PfEMP1 depends on its ability to elicit cross-reactive responses to a substantial number of PfEMP1 variants. We have here evaluated serological PfEMP1 cross-reactivity by immunizing rats with phylogenetically diverse recombinant NTS-DBL-1alpha/x fusion domains from the 3D7 genome parasite emulsified in Montanide ISA 720. Cross-reactivity was elicited to these diverse DBL-1alpha/x domains as measured by ELISA and by immunoblotting. Employing a novel in vivo model of human infected erythrocyte sequestration, immunized animals were challenged with the FCR3S1.2 clone and cross-protection in terms of reduction in lung sequestration amounting to approximately 50% was demonstrated. Our results suggest that immunization with phylogenetically distant DBL-1alpha/x variants, can elicit partial cross-protection to challenge with the parasites harbouring a distant variant. These observations have implications for the design of multi-component vaccines against P. falciparum malaria.
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PMID:Induction of cross-reactive immune responses to NTS-DBL-1alpha/x of PfEMP1 and in vivo protection on challenge with Plasmodium falciparum. 1683 10

Plasmodium vivax invasion of human erythrocytes requires that the ligand domain of the Duffy-binding protein (DBP) recognize its cognate erythrocyte receptor, making DBP a potential target for therapy. The recently determined crystal structure of the orthologous DBP ligand domain of the closely related simian malaria parasite Plasmodium knowlesi provides insight into the molecular basis for receptor recognition and raises important questions about the mechanism of immune evasion employed by the malaria parasite.
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PMID:The crystal structure of P. knowlesi DBPalpha DBL domain and its implications for immune evasion. 1637 20

The early 20th century Southerner lived in a disease environment created by a confluence of poverty, climate and the legacy of slavery. A deadly trio of pellagra, hookworm and malaria enervated the poor Southerner--man, woman and child--creating a dull, weakened people ill equipped to prosper in the modem world. The Northern perceptions of the South as a backward and sickly region were only compounded by the realization that her population was malnourished, infected by worms, and continually plagued by agues and fevers. As historian John Duffy concluded, "As a chronically debilitating disease, it [malaria] shared with the other two the responsibility for the term 'lazy Southerner".
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PMID:Social consequence of disease in the American South, 1900-World War II. 1692 81

Sequestration of Plasmodium falciparum-infected erythrocytes in the placenta is implicated in pathological outcomes of pregnancy-associated malaria (PAM). P. falciparum isolates that sequester in the placenta primarily bind chondroitin sulfate A (CSA). Following exposure to malaria during pregnancy, women in areas of endemicity develop immunity, and so multigravid women are less susceptible to PAM than primigravidae. Protective immunity to PAM is associated with the development of antibodies that recognize diverse CSA-binding, placental P. falciparum isolates. The epitopes recognized by such protective antibodies have not been identified but are likely to lie in conserved Duffy binding-like (DBL) domains, encoded by var genes, that bind CSA. Immunization of mice with the CSA-binding DBL3gamma domain encoded by var1CSA elicits cross-reactive antibodies that recognize diverse CSA-binding P. falciparum isolates and block their binding to placental cryosections under flow. However, CSA-binding isolates primarily express var2CSA, which does not encode any DBLgamma domains. Here, we demonstrate that antibodies raised against DBL3gamma encoded by var1CSA cross-react with one of the CSA-binding domains, DBL3X, encoded by var2CSA. This explains the paradoxical observation made here and earlier that anti-rDBL3gamma sera recognize CSA-binding isolates and provides evidence for the presence of conserved, cross-reactive epitopes in diverse CSA-binding DBL domains. Such cross-reactive epitopes within CSA-binding DBL domains can form the basis for a vaccine that provides protection against PAM.
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PMID:Immunogenicity of Duffy binding-like domains that bind chondroitin sulfate A and protection against pregnancy-associated malaria. 1698 75

Apicomplexan pathogens are obligate intracellular parasites. To enter cells, they must bind with high affinity to host cell receptors and then uncouple these interactions to complete invasion. Merozoites of Plasmodium falciparum, the parasite responsible for the most dangerous form of malaria, invade erythrocytes using a family of adhesins called Duffy binding ligand-erythrocyte binding proteins (DBL-EBPs). The best-characterized P. falciparum DBL-EBP is erythrocyte binding antigen 175 (EBA-175), which binds erythrocyte surface glycophorin A. We report that EBA-175 is shed from the merozoite at around the point of invasion. Shedding occurs by proteolytic cleavage within the transmembrane domain (TMD) at a site that is conserved across the DBL-EBP family. We show that EBA-175 is cleaved by PfROM4, a rhomboid protease that localizes to the merozoite plasma membrane, but not by other rhomboids tested. Mutations within the EBA-175 TMD that abolish cleavage by PfROM4 prevent parasite growth. Our results identify a crucial role for intramembrane proteolysis in the life cycle of this pathogen.
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PMID:Intramembrane proteolysis mediates shedding of a key adhesin during erythrocyte invasion by the malaria parasite. 1700 Aug 79

We compared the serological phenotypic frequencies of ABO, MNSs, and Duffy in 417 blood donors and 309 malaria patients from four Brazilian Amazon areas. Our results suggest no correlation between ABO phenotype and malaria infection in all areas studied. We observed significant correlation between the S +s +, S +s -, and S -s + phenotypes and malaria infection in three areas. Some of the Duffy phenotypes showed significant correlation between donors and malaria patients in different areas. These data are an additional contribution to the establishment of differential host susceptibility to malaria.
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PMID:Frequencies of ABO, MNSs, and Duffy phenotypes among blood donors and malaria patients from four Brazilian Amazon areas. 1703 27

The Plasmodium falciparum erythrocyte membrane protein 1 (PfEMP1) is an important virulence factor on the surface of infected erythrocytes. Naturally acquired antibodies to PfEMP1 expressed by parasites causing severe malaria are suggested to be protective and of major interest for the development of a vaccine against severe disease. In this study, the PfEMP1 expressed by a parasite clone displaying a multiadhesive phenotype associated with severe malaria was well recognized by sera of malaria semi-immune children. The efficiency of the Duffy binding-like 1 alpha (DBL1 alpha) domain of this PfEMP1 was therefore, alone or in combination with two additional DBL1 alpha domains, evaluated as a potential vaccine candidate using both a rodent model and a primate model. Antibodies against the DBL1 alpha domain were generated by immunization with recombinant DBL1 alpha-Semliki Forest virus particles and recombinant protein and analyzed in vitro. The immunized animals were challenged in vivo with various parasite strains or clones. Immunization with the PfEMP1-DBL1 alpha domain abolished the PfEMP1-dependent sequestration of the homologous strain in immunized rats and substantially inhibited parasite adhesion in immunized monkeys. Protection against sequestration of heterologous parasite strains was also confirmed by direct or indirect challenge in the rat model. These results strongly support the use of the DBL1 alpha domain in the development of a vaccine targeting severe malaria.
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PMID:Generation of cross-protective antibodies against Plasmodium falciparum sequestration by immunization with an erythrocyte membrane protein 1-duffy binding-like 1 alpha domain. 1707 52


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