title: Selective upregulation of a single distinctly structured var gene in chondroitin sulphate A-adhering Plasmodium falciparum involved in pregnancy-associated malaria.
abstract: 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.
authors.affiliation: Centre for Medical Parasitology at the Institute for Medical Microbiology and Immunology, University of Copenhagen, Panum Institute 24-2, and Department of Infectious Diseases, Copenhagen University Hospital (Rigshospitalet), Denmark. hecmp@biobase.dk
authors.forename: Ali
authors.initials: A
authors.lastname: Salanti
authors.forename: Trine
authors.initials: T
authors.lastname: Staalsoe
authors.forename: Thomas
authors.initials: T
authors.lastname: Lavstsen
authors.forename: Anja T R
authors.initials: AT
authors.lastname: Jensen
authors.forename: M P Kordai
authors.initials: MP
authors.lastname: Sowa
authors.forename: David E
authors.initials: DE
authors.lastname: Arnot
authors.forename: Lars
authors.initials: L
authors.lastname: Hviid
authors.forename: Thor G
authors.initials: TG
authors.lastname: Theander
mesh_terms: D000328:Adult; D000818:Animals; D000953:Antigens, Protozoan / Q000235:genetics* / Q000378:metabolism; D000954:Antigens, Surface / Q000235:genetics / Q000378:metabolism; D002448:Cell Adhesion; D002648:Child; D002809:Chondroitin Sulfates / Q000378:metabolism*; D004912:Erythrocytes / Q000469:parasitology / Q000502:physiology; D005260:Female; D018503:Genome, Protozoan; D006801:Humans; D016778:Malaria, Falciparum / Q000469:parasitology*; D008297:Male; D005810:Multigene Family; D010920:Placenta / Q000469:parasitology; D010963:Plasmodium falciparum / Q000235:genetics* / Q000378:metabolism; D011247:Pregnancy; D015597:Pregnancy Complications, Parasitic / Q000469:parasitology*; D015800:Protozoan Proteins / Q000235:genetics* / Q000378:metabolism; D014158:Transcription, Genetic; D015854:Up-Regulation
chemical_list: D000953:Antigens, Protozoan; D000954:Antigens, Surface; D015800:Protozoan Proteins; D002809:Chondroitin Sulfates