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Evidence for the Involvement of VAR2CSA in Pregnancy-associated Malaria

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      Abstract

      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, VSA PAM, which can be serologically classified as sex specific and parity dependent. It is sex specific because men from malaria-endemic areas do not develop VSA PAM antibodies; it is parity dependent because women acquire anti-VSA PAM immunoglobulin (Ig) G as a function of parity. Previously, it was shown that transcription of var2csa is up-regulated in placental parasites and parasites selected for CSA binding. Here, we show the following: (a) that VAR2CSA is expressed on the surface of CSA-selected IEs; (b) that VAR2CSA is recognized by endemic plasma in a sex-specific and parity-dependent manner; (c) that high anti-VAR2CSA IgG levels can be found in pregnant women from both West and East Africa; and (d) that women with high plasma levels of anti-VAR2CSA IgG give birth to markedly heavier babies and have a much lower risk of delivering low birth weight children than women with low levels.

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      Most cited references 39

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      Genome sequence of the human malaria parasite Plasmodium falciparum.

      The parasite Plasmodium falciparum is responsible for hundreds of millions of cases of malaria, and kills more than one million African children annually. Here we report an analysis of the genome sequence of P. falciparum clone 3D7. The 23-megabase nuclear genome consists of 14 chromosomes, encodes about 5,300 genes, and is the most (A + T)-rich genome sequenced to date. Genes involved in antigenic variation are concentrated in the subtelomeric regions of the chromosomes. Compared to the genomes of free-living eukaryotic microbes, the genome of this intracellular parasite encodes fewer enzymes and transporters, but a large proportion of genes are devoted to immune evasion and host-parasite interactions. Many nuclear-encoded proteins are targeted to the apicoplast, an organelle involved in fatty-acid and isoprenoid metabolism. The genome sequence provides the foundation for future studies of this organism, and is being exploited in the search for new drugs and vaccines to fight malaria.
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        The large diverse gene family var encodes proteins involved in cytoadherence and antigenic variation of Plasmodium falciparum-infected erythrocytes.

        The human malaria parasite Plasmodium falciparum evades host immunity by varying the antigenic and adhesive character of infected erythrocytes. We describe a large and extremely diverse family of P. falciparum genes (var) that encode 200-350 kDa proteins having the expected properties of antigenically variant adhesion molecules. Predicted amino acid sequences of var genes show a variable extracellular segment with domains having receptor-binding features, a transmembrane sequence, and a terminal segment that is a probable submembrane anchor. There are 50-150 var genes on multiple parasite chromosomes, and some are in clustered arrangements. var probes detect two classes of transcripts in steady-state RNA: 7-9 kb var transcripts, and an unusual family of 1.8-2.4 kb transcripts that may be involved in expression or rearrangements of var genes.
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          Selective upregulation of a single distinctly structured var gene in chondroitin sulphate A-adhering Plasmodium falciparum involved in pregnancy-associated malaria.

          Cytoadhesion of infected red blood cells (iRBC) is mediated through parasite-encoded, clonally variant surface antigens (VSA) and is a central process in the pathogenesis of Plasmodium falciparum malaria. Pregnancy-associated malaria (PAM) has been linked to VSA-mediated adhesion of iRBC to the glycosaminoglycan chondroitin sulphate A (CSA) in the placental intervillous space. Several studies have pointed to members of the PfEMP1 VSA family as mediators of CSA-specific iRBC sequestration in the placenta. Here, we report marked upregulation of a single var gene in several P. falciparum parasite isolates after selection for adhesion to CSA in vitro. The gene belongs to a highly conserved and common var gene subfamily (var2csa). The var2csa genes are structurally distinct from all other var genes in the parasite genome in lacking both CIDR and DBL-gamma domains. These domains have previously been implicated in PfEMP1-mediated adhesion to CD36 and CSA. We also show that var2csa was transcribed at higher levels in three placental parasite isolates compared with transcription in parasites from peripheral blood of two children with P. falciparum malaria. This var gene thus has the properties expected of a gene encoding the parasite adhesion molecule that initiates the pathology associated with PAM.
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            Author and article information

            Affiliations
            [1 ]Centre for Medical Parasitology, Department of Medical Microbiology and Immunology, University of Copenhagen
            [2 ]Department of Infectious Diseases, Copenhagen University Hospital, 2200 Copenhagen, Denmark
            [3 ]Noguchi Memorial Institute for Medical Research, University of Ghana, 80108 Legon, Ghana
            [4 ]Kenya Medical Research Institute, Centre for Geographic Medicine Research, Coast Kilifi, Kenya
            Author notes

            Address correspondence to Ali Salanti, Centre for Medical Parasitology, Dept. of Medical Microbiology and Immunology, Panum Institute 24-2, Blegdamsvej 3, 2200 Copenhagen, Denmark. Phone: 45-35-32-76-76; Fax: 45-35-32-78-51; email: salanti@ 123456cmp.dk

            Journal
            J Exp Med
            The Journal of Experimental Medicine
            The Rockefeller University Press
            0022-1007
            1540-9538
            1 November 2004
            : 200
            : 9
            : 1197-1203
            2211857
            20041579
            10.1084/jem.20041579
            15520249
            Copyright © 2004, The Rockefeller University Press
            Categories
            Brief Definitive Report

            Medicine

            plasmodium falciparum, vaccine, pfemp1, var gene, var2csa

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