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

At the present time more is known about barriers to transmission of infectious agents between species than barriers to transmission within the same species. However differences in resistance to infection have been well-established within given species of various plants and domestic farm animals. Unsurprisingly several similar mechanisms have been observed in humans. A well-known human example of genetic protection is resistance to malaria in endemic areas which has been associated with polymorphism in alpha and beta chain globulin genes, cytoskeleton proteins, and protein/receptors on the surface of red blood cells. Studies regarding infection by Schistosoma mansoni show that the extent of infection depends largely on each individual's intrinsic resistance under the control of a single major gene which has now been located on q31-33 locus of the long arm of chromosome 5. This locus harbors several genes involved in differentiation of auxiliary T lymphocytes. With regard to HIV infection it has been known for several years that a small but significant number of individuals are relatively resistant. This resistance has been attributed to deletion of the gene coding for the chemokine receptor used by the virus as a co-receptor to infect macrophage.
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PMID:[Genetic predisposition to infectious diseases]. 951 72

The Duffy blood group locus, which encodes a chemokine receptor, is characterized by three alleles-FY*A, FY*B, and FY*O. The frequency of the FY*O allele, which corresponds to the absence of Fy antigen on red blood cells, is at or near fixation in most sub-Saharan African populations but is very rare outside Africa. The FST value for the FY*O allele is the highest observed for any allele in humans, providing strong evidence for the action of natural selection at this locus. Homozygosity for the FY*O allele confers complete resistance to vivax malaria, suggesting that this allele has been the target of selection by Plasmodium vivax or some other infectious agent. To characterize the signature of directional selection at this locus, we surveyed DNA sequence variation, both in a 1.9-kb region centered on the FY*O mutation site and in a 1-kb region 5-6 kb away from it, in 17 Italians and in a total of 24 individuals from five sub-Saharan African populations. The level of variation across both regions is two- to threefold lower in the Africans than in the Italians. As a result, the pooled African sample shows a significant departure from the neutral expectation for the number of segregating sites, whereas the Italian sample does not. The FY*O allele occurs on two major haplotypes in three of the five African populations. This finding could be due to recombination, recurrent mutation, population structure, and/or mutation accumulation and drift. Although we are unable to distinguish among these alternative hypotheses, it is likely that the two major haplotypes originated prior to selection on the FY*O mutation.
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PMID:Detection of the signature of natural selection in humans: evidence from the Duffy blood group locus. 1076 51

A fundamental question for the intensivist is why some individuals but not others succumb to life-threatening infection. A growing body of evidence indicates that both the risk of acquiring infection and the risk of developing severe complications are determined by host genetic factors. These include a number of single gene defects with devastating consequences, e. g. interferon-gamma receptor mutations that lead to fatal infections with ubiquitous mycobacteria, but such examples are relatively rare. Of greater importance for routine clinical practice is the potentially vast number of genetic variants with subtle effects on the regulation or function of specific immunological, physiological and metabolic mediators. Such polygenic traits do not obey simple patterns of familial segregation seen for monogenic disorders, and their clinical investigation is further complicated by the environmental variability of infectious exposure. Recent advances in this field have therefore largely stemmed from hospital-based case-controlled studies that have uncovered disease associations with specific DNA polymorphisms in candidate gene regions. For example, tumour necrosis factor polymorphisms have been associated with susceptibility to malaria and other infections; chemokine receptor polymorphisms with susceptibility to HIV; natural resistance-associated macrophage protein 1 with tuberculosis; and mannose binding lectin polymorphisms with meningococcal disease. A much greater number of genetic associations will emerge as the full extent of human genomic diversity becomes known. The challenge for clinical investigators is to generate an epidemiological framework for population- and family-based association studies, which is sufficiently robust to exclude population artifacts and sufficiently powerful to be able to dissect true disease-causing polymorphisms from linked genetic markers. In the long term this approach promises to identify host mediators that are critical for pathogenesis and immunity and to yield molecular insights into the complex processes of human gene regulation. This information is likely to be of considerable value in designing more effective approaches to the treatment and prevention of life-threatening infectious disease.
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PMID:Genetic dissection of the molecular pathogenesis of severe infection. 1078 64

Chemokines are small peptides that are potent activators and chemoattractants for leukocyte subpopulations and some nonhemopoietic cells. Their actions are mediated by a family of 7-transmembrane G-protein-coupled receptors, the size of which has grown considerably in recent years and now includes 18 members. Chemokine receptor expression on different cell types and their binding and response to specific chemokines are highly variable. Significant advances have been made in understanding the regulation of chemokine receptor expression and the intracellular signaling mechanisms used in bringing about cell activation. Chemokine receptors have also recently been implicated in several disease states including allergy, psoriasis, atherosclerosis, and malaria. However, most fascinating has been the observation that some of these receptors are used by human immunodeficiency virus type 1 in gaining entry into permissive cells. This review will discuss structural and functional aspects of chemokine receptor biology and will consider the roles these receptors play in inflammation and in infectious diseases.
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PMID:Chemokine receptors and their role in inflammation and infectious diseases. 1080 66

Infection with Plasmodium berghei ANKA induces cerebral malaria in susceptible mice. Brain-sequestered CD8(+) T cells are responsible for this pathology. We have evaluated the role of CCR2, a chemokine receptor expressed on CD8(+) T cells. Infected CCR2-deficient mice were as susceptible to cerebral malaria as wild-type mice were, and CD8(+) T-cell migration to the brain was not abolished.
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PMID:Chemokine receptor CCR2 is not essential for the development of experimental cerebral malaria. 1276 Nov 55

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.
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PMID:The Duffy antigen/receptor for chemokines (DARC) regulates prostate tumor growth. 1639 68

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.
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PMID:Duffy blood group and malaria. 1760 93

Chemokine receptors are G protein-coupled receptors (GPCRs) that, through their ability to regulate chemotaxis by responding to small chemoattractant peptides termed chemokines, are involved in the development, maintenance, and functional activities of the immune system. In addition, members of the chemokine receptor family have been implicated in a number of other physiological and pathological processes, including human immunodeficiency virus infection and malaria. These activities are dependent on receptor expression at the cell surface and cellular events that reduce the cell-surface expression of chemokine receptors can abrogate these activities. Moreover, internalization of chemokine receptors by endocytosis is necessary for both receptor degradation and recycling, key regulatory processes that determine cell-surface expression levels. Here we provide detailed methods for the quantitative analysis of CCR5 endocytosis and recycling by flow cytometry, as well as fluorescence and electron microscopic procedures to analyze the endocytosis and intracellular trafficking of CCR5 by immunolabeling of cells or cryosections. In principle, the same approaches can be used for analyzing other chemokine receptors and other GPCR or non-GPCR cell-surface proteins.
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PMID:Analysis of chemokine receptor endocytosis and intracellular trafficking. 1944 35

The Duffy Antigen/Receptor for Chemokine (DARC) is a seven segment transmembrane protein. It was firstly discovered as a blood group antigen and was the first specific gene locus assigned to a specific autosome in man. It became more famous as an erythrocyte receptor for malaria parasites (Plasmodium vivax and Plasmodium knowlesi), and finally for chemokines. DARC is an unorthodox chemokine receptor as (i) it binds chemokines of both CC and CXC classes and (ii) it lacks the Asp-Arg-Tyr consensus motif in its second cytoplasmic loop hence cannot couple to G proteins and activate their signaling pathways. DARC had also been associated to cancer progression, numerous inflammatory diseases, and possibly to AIDS. In this review, we will summarize important biological data on DARC. Then we shall focus on recent development of the elaboration and analyzes of structural models of DARC. We underline the difficulty to propose pertinent structural models of transmembrane protein using comparative modeling process, and other dedicated approaches as the Protein Blocks. The chosen structural models encompass most of the biochemical data known to date. Finally, we present recent development of protein-protein docking between DARC structural models and CXCL-8 structures. We propose a hierarchical search based on separated rigid and flexible docking.
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PMID:In silico studies on DARC. 1951 83

The ecology, behaviour and genetics of our closest living relatives, the nonhuman primates, should help us to understand the evolution of our own lineage. Although a large amount of data has been amassed on primate ecology and behaviour, much less is known about the functional and evolutionary genetic aspects of primate biology, especially in wild primates. As a result, even in well-studied populations in which nongenetic factors that influence adaptively important characteristics have been identified, we have almost no understanding of the underlying genetic basis for such traits. Here, we report on the functional consequences of genetic variation at the malaria-related FY (DARC) gene in a well-studied population of yellow baboons (Papio cynocephalus) living in Amboseli National Park in Kenya. FY codes for a chemokine receptor normally expressed on the erythrocyte surface that is the known entry point for the malarial parasite Plasmodium vivax. We identified variation in the cis-regulatory region of the baboon FY gene that was associated with phenotypic variation in susceptibility to Hepatocystis, a malaria-like pathogen that is common in baboons. Genetic variation in this region also influenced gene expression in vivo in wild individuals, a result we confirmed using in vitro reporter gene assays. The patterns of genetic variation in and around this locus were also suggestive of non-neutral evolution, raising the possibility that the evolution of the FY cis-regulatory region in baboons has exhibited both mechanistic and selective parallels with the homologous region in humans. Together, our results represent the first reported association and functional characterization linking genetic variation and a complex trait in a natural population of nonhuman primates.
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PMID:Evolution of a malaria resistance gene in wild primates. 1955 36


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