VAR2CSA is the principal ligand for chondroitin sulfate A in two allogeneic isolates of Plasmodium falciparum.

Malaria during pregnancy causes serious disease that is associated with sequestration in the placenta of Plasmodium falciparum infected erythrocytes that adhere to several host receptors, including chondroitin sulfate A (CSA). The principal CSA binding ligand associated with placental sequestration is the P. falciparum erythrocyte membrane protein 1 (PfEMP1), encoded by the var2csa gene. We disrupted the var2csa gene in two allogeneic parasites and ablated CSA binding. However, in one parasite line we were able to re-select for adhesion to bovine trachea CSA associated with transcription of two var genes, var-CS2 and varP. Parasites transcribing parts of var-CS2 and varP were present in the placentae of some infected women but the mutant parasites that transcribed var-CS2 and varP were recognized by sera from men and pregnant women independent of parity. This work raises the possibility that the PfEMP1 molecules encoded by var-CS2 and varP may be minor contributors to placental malaria but also confirms the importance of the immunodominant, conserved var2csa PfEMP1s in pregnancy associated malaria and strengthens the case for var2csa as a pregnancy-specific malaria vaccine.

[1]  Michael Lanzer,et al.  A single member of the Plasmodium falciparum var multigene family determines cytoadhesion to the placental receptor chondroitin sulphate A , 2005, EMBO reports.

[2]  E. J. Mann,et al.  Antibodies to variant surface antigens of Plasmodium falciparum-infected erythrocytes and adhesion inhibitory antibodies are associated with placental malaria and have overlapping and distinct targets. , 2004, The Journal of infectious diseases.

[3]  R. Anders,et al.  Adherence of infected erythrocytes to venular endothelium selects for antigenic variants of Plasmodium falciparum. , 1992, Journal of immunology.

[4]  M. Molyneux,et al.  Adhesion of Plasmodium falciparum-infected erythrocytes to hyaluronic acid in placental malaria , 2000, Nature Medicine.

[5]  Mats Wahlgren,et al.  Developmental selection of var gene expression in Plasmodium falciparum , 1998, Nature.

[6]  B. Gamain,et al.  Molecular basis for the dichotomy in Plasmodium falciparum adhesion to CD36 and chondroitin sulfate A , 2002, Proceedings of the National Academy of Sciences of the United States of America.

[7]  A. Cowman,et al.  Multiple var gene transcripts are expressed in Plasmodium falciparum infected erythrocytes selected for adhesion. , 2001, Molecular and biochemical parasitology.

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

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

[10]  M. Molyneux,et al.  Plasmodium falciparum isolates from infected pregnant women and children are associated with distinct adhesive and antigenic properties. , 1999, The Journal of infectious diseases.

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

[12]  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.

[13]  C. Menéndez,et al.  The burden of malaria in pregnancy in malaria-endemic areas. , 2001, The American journal of tropical medicine and hygiene.

[14]  A. Craig,et al.  Analysis of adhesive domains from the A4VAR Plasmodium falciparum erythrocyte membrane protein-1 identifies a CD36 binding domain. , 1998, Molecular and biochemical parasitology.

[15]  B. Gamain,et al.  Identification of multiple chondroitin sulfate A (CSA)-binding domains in the var2CSA gene transcribed in CSA-binding parasites. , 2005, The Journal of infectious diseases.

[16]  Danny W. Wilson,et al.  Broad analysis reveals a consistent pattern of var gene transcription in Plasmodium falciparum repeatedly selected for a defined adhesion phenotype , 2005, Molecular microbiology.

[17]  S. Kyes,et al.  MicroReview: The role of Plasmodium falciparum var genes in malaria in pregnancy , 2004, Molecular microbiology.

[18]  Thor G. Theander,et al.  Evidence for the Involvement of VAR2CSA in Pregnancy-associated Malaria , 2004, The Journal of experimental medicine.

[19]  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.

[20]  E. J. Mann,et al.  Cross-Reactive Surface Epitopes on Chondroitin Sulfate A-Adherent Plasmodium falciparum-Infected Erythrocytes Are Associated with Transcription of var2csa , 2005, Infection and Immunity.

[21]  Manoj T. Duraisingh,et al.  Heterochromatin Silencing and Locus Repositioning Linked to Regulation of Virulence Genes in Plasmodium falciparum , 2005, Cell.

[22]  T. Triglia,et al.  Negative selection of Plasmodium falciparum reveals targeted gene deletion by double crossover recombination. , 2002, International journal for parasitology.

[23]  G. Bentley,et al.  Functional and immunological characterization of a duffy binding-like- gamma domain from Plasmodium falciparum erythrocyte membrane protein-1 expressed by a placental isolate. , 2005, Journal of Infectious Diseases.

[24]  M. Molyneux,et al.  Placental monocyte infiltrates in response to Plasmodium falciparum malaria infection and their association with adverse pregnancy outcomes. , 2003, The American journal of tropical medicine and hygiene.

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

[26]  A. Cowman,et al.  Transcription of multiple var genes by individual, trophozoite‐stage Plasmodium falciparum cells expressing a chondroitin sulphate A binding phenotype , 2002, Molecular microbiology.

[27]  J. Reeder,et al.  Identification of Glycosaminoglycan Binding Domains in Plasmodium falciparum Erythrocyte Membrane Protein 1 of a Chondroitin Sulfate A-Adherent Parasite , 2000, Infection and Immunity.

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

[29]  S. Looareesuwan,et al.  Cytoadherence characteristics of Plasmodium falciparum isolates from Thailand: evidence for chondroitin sulfate a as a cytoadherence receptor. , 1996, The American journal of tropical medicine and hygiene.

[30]  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.

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

[32]  Joseph D. Smith,et al.  Evidence for the importance of genetic structuring to the structural and functional specialization of the Plasmodium falciparum var gene family , 2003, Molecular microbiology.