Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts:   Target Concepts:
Query: UMLS:C0024530 (malaria)
 44,886 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

The Duffy antigen (Fy) is necessary for Plasmodium vivax invasion of human erythrocytes. Some populations have a highly prevalent Fy-negative phenotype; such persons are naturally protected from P. vivax blood infection but are expected to completely support the P. vivax pre-erythrocytic cycle, representing a valuable model for studying the immune response during these parasitic stages. We typed 214 individuals, mostly Afro-Colombians, from a P. vivax-endemic area for Fy expression and determined the antibody response to P. vivax pre-erythrocytic (sporozoites and CS) and blood-stage antigens (blood forms, P. vivax merozoite surface protein 1, and P. vivax Duffy binding protein [PvDBP]). Antibody titers to P. vivax circumsporozoite protein, P11, and N-terminal peptides and the number of responders were similar in Fy-negative and Fy-positive individuals. The number of responders to sporozoites, blood forms, and PvDBP were different between these groups. Thus, Fy-negative individuals from malaria-endemic areas can be used to study the immune response to the P. vivax liver phase without interference of the erythrocytic cycle.
 ...
PMID:Antibody response to Plasmodium vivax antigens in Fy-negative individuals from the Colombian Pacific coast. 1629 66

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.
 ...
PMID:Structural basis for Duffy recognition by the malaria parasite Duffy-binding-like domain. 1687 18

The Duffy antigen/receptor for chemokines (DARC) is a promiscuous chemokine receptor that binds to members of the CXC chemokine family possessing angiogenic properties. The DARC is expressed on erythrocytes and endothelial cells and is required for Plasmodium vivax infection of erythrocytes. Approximately 70% of African-Americans lack erythrocyte expression of the DARC as a genetic mechanism of protection against malaria infection. African-American men have a 60% greater incidence of prostate cancer and a 2-fold higher mortality rate than Caucasian men. Using a transgenic model of prostate cancer with DARC-deficient mice, we tested the hypothesis that lack of DARC expression on erythrocytes contributes to enhanced prostate tumor growth. In vitro, erythrocytes from wild-type mice but not DARC-deficient mice cleared angiogenic chemokines produced by prostate cancer cells and reduced endothelial cell chemotaxis. In vivo, tumors from DARC-deficient mice had higher intra-tumor concentrations of angiogenic chemokines, increased tumor vessel density, and greatly augmented prostate tumor growth. The data suggest that the DARC functions to clear angiogenic CXC chemokines from the prostate tumor microcirculation and that the lack of erythroid DARC, as occurs in the majority of African-Americans, may be a contributing factor to the increased mortality to prostate cancer in this population.
 ...
PMID:The Duffy antigen/receptor for chemokines (DARC) regulates prostate tumor growth. 1639 68

An effective malaria vaccine will probably require the delivery of multiple antigens that induce several layers of immunity. Malaria antigens expressed on the surface and in apical organelles of blood-stage merozoites are potential vaccine candidates given their importance in the invasion of erythrocytes. The present study examined the kinetics of humoral response in BALB/c mice following immunization with combination of two blood-stage Plasmodium vivax invasion related molecules, the N-terminal, cysteine-rich region II of P. vivax Duffy binding protein (PvRII) and the 19kDa C-terminal region of merozoite surface protein 1 (PvMSP1(19)) formulated with Montanide ISA 720 and alhydrogel. Immunization with combination of recombinant PvRII and PvMSP1(19) formulated with the Montanide ISA 720 elicited higher antibody titer compared to the alhydrogel formulation. In case of both the adjuvants tested, combination of PvRII and PvMSP1(19) did not result in suppression of antibody response against either antigen when compared to immunization with individual antigens alone. Analysis of IgG subclasses showed that combination of both the recombinant proteins induced a mixed Th1/Th2-type response with almost all IgG subtypes being expressed in equivalent amount. Antibodies elicited against PvRII showed significant inhibitory effect on the binding of PvRII to recombinant Duffy antigen receptor for chemokines (DARC) in an in vitro binding assay. The results of the present study provide a rationale for a combination vaccine against P. vivax malaria based on PvMSP1(19) and PvRII.
 ...
PMID:Immunogenicity of Plasmodium vivax combination subunit vaccine formulated with human compatible adjuvants in mice. 1754 79

Very important progress has been made over the last years in understanding the Duffy blood group system and its complexity. The Duffy blood group antigen serves not only as blood group antigen, but also as a receptor for a family of proinflammatory cytokines termed chemokines, and as a receptor for Plasmodium vivax malaria parasites. The Duffy antigen has been termed the "Duffy Antigen Receptor for Chemokines" (DARC) or the Duffy chemokine receptor. DARC might play a role as a scanvenger on the red blood cell surface to eliminate excess of toxic chemokines produced in some pathologic situations [48]. Plasmodium vivax (P. vivax) causes approximately between 70 and 80 million cases of malaria per year and is the most amply distributed human malaria in the world [51]. Individuals with the Duffy-negative phenotype are resistant to P. vivax invasion, and the molecular mechanism that gives rise to the phenotype Fy(a - b - ) in black individuals has been associated with a point mutation - 33TC expressed in homozigosity in the FYB allele [5]. Despite P. vivax be widespread throughout the tropical and subtropical world, it is absent from West Africa, where more than 95% of the population is Duffy negative. Recently, this point mutation has been described in heterozigosity in the FYA allele in others malaria endemic regions [7, 8], and until now we do not know if it confers a certain degree of protection against P. vivax infection.
 ...
PMID:Duffy blood group and malaria. 1760 93

Tyrosine sulfation is one of the most common post-translational modifications in secreted and transmembrane proteins and a key modulator of extracellular protein-protein interactions. Several proteins known to be tyrosine sulfated play important roles in physiological processes, and in some cases a direct link between protein function and tyrosine sulfation has been established. In blood coagulation, tyrosine sulfation of factor VIII is required for efficient binding of von Willebrand factor; in leukocyte adhesion, tyrosine sulfation of the P-selectin glycoprotein ligand-1 mediates high-affinity binding to P-selectin; and in leukocyte chemotaxis, tyrosine sulfation of chemokine receptors is required for optimal interaction with chemokine ligands. Furthermore, tyrosine sulfation has been implicated in several infectious diseases. In particular, tyrosine sulfation of the HIV-1 co-receptor CCR5 is required for viral entry into host cells and tyrosine sulfation of the Duffy antigen/receptor for chemokines is crucial for erythrocyte invasion by the malaria parasite plasmodium vivax. Despite increasing interest in tyrosine sulfation in recent years, the sulfoproteome still remains largely unexplored. To date, only a relatively small number of sulfotyrosine-containing peptides and proteins have been identified, and a specific role for tyrosine sulfation has not been established for most of these. Here, we provide an overview of the biology and enzymology of tyrosine sulfation and discuss recent developments in preparative and analytical methods that are central to sulfoproteome research.
 ...
PMID:Toward a framework for sulfoproteomics: Synthesis and characterization of sulfotyrosine-containing peptides. 1768 Jul 2

Consanguineous marriages are usually socially driven and can be genetically harmful. The detrimental effects of inbreeding are the consequence of homozygosity of harmful genes. On the other hand, beneficial effects of inbreeding, theoretically, could be expected in those who are homozygous for protective recessive and codominant genes. Here, we argue that the most common monogenetic conditions in humans, namely, alpha-thalassemia, glucose-6-phosphate dehydrogenase (G6PD) deficiency, hemoglobin C, and Duffy antigen negative red blood cells, which have evolved under pressure from malaria, had their survival and selection enhanced by consanguineous marriages in malaria-infested regions of the world. This hypothesis is supported by several observations. First, the presence of two mutations in homozygotes involving the listed conditions (except G6PD deficiency) imparts better protection against malaria than the presence of one or no mutation (heterozygous or normal genotypes, respectively); consanguinity increases the number of homozygotes, especially at low allele frequency. For G6PD deficiency, inbreeding could increase the allele frequency of the G6PD-deficient allele. Second, there is overlap between, on the one hand, the geographic distributions of malaria, thalassemias, and other red blood cell conditions that protect against malaria and, on the other hand, consanguineous marriages. Third, the distribution of different intensities of malaria infestation is matched with the frequency of human inbreeding. These observations, taken together, offer strong support to the hypothesis that the culture of consanguineous marriages and the genetics of protection against malaria have co-evolved by fostering survival against malaria through better retention of protective genes in the extended family.
 ...
PMID:Genetic benefits of consanguinity through selection of genotypes protective against malaria. 1802 11

Individuals residing in malaria-endemic regions acquire protective immunity after repeated infection with malaria parasites; however, mechanisms of protective immunity and their immune correlates are poorly understood. Blood-stage infection with Plasmodium vivax depends completely on interaction of P. vivax Duffy-binding protein (PvDBP) with the Duffy antigen on host erythrocytes. Here, we performed a prospective cohort treatment/reinfection study of children (5-14 years) residing in a P. vivax-endemic region of Papua New Guinea (PNG) in which children were cleared of blood-stage infection and then examined biweekly for reinfection for 25 weeks. To test the hypothesis that naturally acquired binding inhibitory antibodies (BIAbs) targeting PvDBP region II (PvDBPII) provide protection against P. vivax infection, we used a quantitative receptor-binding assay to distinguish between antibodies that merely recognize PvDBP and those that inhibit binding to Duffy. The presence of high-level BIAbs (>90% inhibition of PvDBPII-Duffy binding, n = 18) before treatment was associated with delayed time to P. vivax reinfection diagnosed by light microscopy (P = 0.02), 55% reduced risk of P. vivax reinfection (Hazard's ratio = 0.45, P = 0.04), and 48% reduction in geometric mean P. vivax parasitemia (P < 0.001) when compared with children with low-level BIAbs (n = 148). Further, we found that stable, high-level BIAbs displayed strain-transcending inhibition by reducing reinfection with similar efficiency of PNG P. vivax strains characterized by six diverse PvDBPII haplotypes. These observations demonstrate a functional correlate of protective immunity in vivo and provide support for developing a vaccine against P. vivax malaria based on PvDBPII.
 ...
PMID:Naturally acquired Duffy-binding protein-specific binding inhibitory antibodies confer protection from blood-stage Plasmodium vivax infection. 1852 22

A mutation in the Duffy antigen (DARC) that abrogates receptor expression and gives profound protection against some malaria species has become almost universal in African populations. He et al. (2008) show that this polymorphism also leads to significantly increased susceptibility to HIV-1 infection but, paradoxically, to prolonged survival in HIV-1-infected subjects.
 ...
PMID:HIV and chemokine binding to red blood cells--DARC matters. 1862 Oct 10

Duffy antigen receptor for chemokines (DARC) expressed on red blood cells (RBCs) influences plasma levels of HIV-1-suppressive and proinflammatory chemokines such as CCL5/RANTES. DARC is also the RBC receptor for Plasmodium vivax. Africans with DARC -46C/C genotype, which confers a DARC-negative phenotype, are resistant to vivax malaria. Here, we show that HIV-1 attaches to RBCs via DARC, effecting trans-infection of target cells. In African Americans, DARC -46C/C is associated with 40% increase in the odds of acquiring HIV-1. If extrapolated to Africans, approximately 11% of the HIV-1 burden in Africa may be linked to this genotype. After infection occurs, however, DARC-negative RBC status is associated with slower disease progression. Furthermore, the disease-accelerating effect of a previously described CCL5 polymorphism is evident only in DARC-expressing and not in DARC-negative HIV-infected individuals. Thus, DARC influences HIV/AIDS susceptibility by mediating trans-infection of HIV-1 and by affecting both chemokine-HIV interactions and chemokine-driven inflammation.
 ...
PMID:Duffy antigen receptor for chemokines mediates trans-infection of HIV-1 from red blood cells to target cells and affects HIV-AIDS susceptibility. 1945 42


<< Previous 1 2 3 4 5 6 7 Next >>