Evidence for the Involvement of VAR2CSA in Pregnancy-associated Malaria

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-VSAPAM 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.

[1]  T. Theander,et al.  Plasma Antibodies from Malaria-Exposed Pregnant Women Recognize Variant Surface Antigens on Plasmodium falciparum-Infected Erythrocytes in a Parity-Dependent Manner and Block Parasite Adhesion to Chondroitin Sulfate A1 , 2000, The Journal of Immunology.

[2]  M. Wahlgren,et al.  The 3D7var5.2 (var COMMON) type var gene family is commonly expressed in non-placental Plasmodium falciparum malaria. , 2003, Molecular and biochemical parasitology.

[3]  T. Theander,et al.  Sub-grouping of Plasmodium falciparum 3D7 var genes based on sequence analysis of coding and non-coding regions , 2003, Malaria Journal.

[4]  B. Gamain,et al.  Identification of a 67‐amino‐acid region of the Plasmodium falciparum variant surface antigen that binds chondroitin sulphate A and elicits antibodies reactive with the surface of placental isolates , 2004, Molecular microbiology.

[5]  R. Leke,et al.  Acquisition and decay of antibodies to pregnancy-associated variant antigens on the surface of Plasmodium falciparum-infected erythrocytes that protect against placental parasitemia. , 2001, The Journal of infectious diseases.

[6]  M. Kozak,et al.  Pushing the limits of the scanning mechanism for initiation of translation , 2002, Gene.

[7]  M. Fried,et al.  Two DBLgamma subtypes are commonly expressed by placental isolates of Plasmodium falciparum. , 2002, Molecular and biochemical parasitology.

[8]  S. Sharp,et al.  Plasmodium falciparum Associated with Severe Childhood Malaria Preferentially Expresses PfEMP1 Encoded by Group A var Genes , 2004, The Journal of experimental medicine.

[9]  Patrick E. Duffy,et al.  Adherence of Plasmodium falciparum to Chondroitin Sulfate A in the Human Placenta , 1996, Science.

[10]  Jonathan E. Allen,et al.  Genome sequence of the human malaria parasite Plasmodium falciparum , 2002, Nature.

[11]  J. Rowe,et al.  Nonspecific Immunoglobulin M Binding and Chondroitin Sulfate A Binding Are Linked Phenotypes of Plasmodium falciparum Isolates Implicated in Malaria during Pregnancy , 2003, Infection and Immunity.

[12]  M. Wahlgren,et al.  The 3D7var5.2 (varCOMMON) type var gene family is commonly expressed in non-placental Plasmodium falciparum malaria , 2003 .

[13]  H. Beck,et al.  Plasmodium falciparum: cloned and expressed CIDR domains of PfEMP1 bind to chondroitin sulfate A. , 2000, Experimental parasitology.

[14]  A. Cowman,et al.  The adhesion of Plasmodium falciparum-infected erythrocytes to chondroitin sulfate A is mediated by P. falciparum erythrocyte membrane protein 1. , 1999, Proceedings of the National Academy of Sciences of the United States of America.

[15]  S. Kyes,et al.  Identification of a conserved Plasmodium falciparum var gene implicated in malaria in pregnancy. , 2002, The Journal of infectious diseases.

[16]  T. Theander,et al.  A sub-family of common and highly conserved Plasmodium falciparum var genes. , 2002, Molecular and biochemical parasitology.

[17]  T. Theander,et al.  In vitro selection of Plasmodium falciparum 3D7 for expression of variant surface antigens associated with severe malaria in African children , 2003, Parasite immunology.

[18]  J. Gysin,et al.  Chondroitin-4-Sulfate Impairs In Vitro and In Vivo Cytoadherence of Plasmodium falciparum Infected Erythrocytes , 1997, Molecular medicine.

[19]  François Nosten,et al.  Maternal antibodies block malaria , 1998, Nature.

[20]  T. Theander,et al.  Lack of Gender-Specific Antibody Recognition of Products from Domains of a var Gene Implicated in Pregnancy-Associated Plasmodium falciparum Malaria , 2003, Infection and Immunity.

[21]  Y. Sterkers,et al.  Sequestration of Plasmodium falciparum-infected erythrocytes to chondroitin sulfate A, a receptor for maternal malaria: monoclonal antibodies against the native parasite ligand reveal pan-reactive epitopes in placental isolates. , 2002, Blood.

[22]  M. Fried,et al.  Antibodies That Inhibit Plasmodium falciparum Adhesion to Chondroitin Sulfate A Are Associated with Increased Birth Weight and the Gestational Age of Newborns , 2003, Infection and Immunity.

[23]  Thomas Lavstsen,et al.  Selective upregulation of a single distinctly structured var gene in chondroitin sulphate A‐adhering Plasmodium falciparum involved in pregnancy‐associated malaria , 2003, Molecular microbiology.

[24]  M. Wahlgren,et al.  Role of Nonimmune IgG Bound to PfEMP1 in Placental Malaria , 2001, Science.

[25]  Y. Sterkers,et al.  Immunization with recombinant duffy binding-like-gamma3 induces pan-reactive and adhesion-blocking antibodies against placental chondroitin sulfate A-binding Plasmodium falciparum parasites. , 2003, The Journal of infectious diseases.

[26]  B. Gamain,et al.  Plasmodium falciparum domain mediating adhesion to chondroitin sulfate A: a receptor for human placental infection. , 1999, Proceedings of the National Academy of Sciences of the United States of America.

[27]  K. Marsh,et al.  Malaria in pregnancy: adverse effects on haemoglobin levels and birthweight in primigravidae and multigravidae , 2001, Tropical medicine & international health : TM & IH.

[28]  Kevin Marsh,et al.  Variant surface antigen-specific IgG and protection against clinical consequences of pregnancy-associated Plasmodium falciparum malaria , 2004, The Lancet.

[29]  B. Brabin.  An analysis of malaria in pregnancy in Africa. , 1983, Bulletin of the World Health Organization.

[30]  X. Su,et al.  The large diverse gene family var encodes proteins involved in cytoadherence and antigenic variation of plasmodium falciparum-infected erythrocytes , 1995, Cell.

[31]  T. Theander,et al.  Naturally acquired antibodies to the glutamate-rich protein are associated with protection against Plasmodium falciparum malaria. , 2000, The Journal of infectious diseases.