Selective upregulation of a single distinctly structured <i>var</i> gene in chondroitin sulphate A‐adhering <i>Plasmodium falciparum</i> involved in pregnancy‐associated malaria

TLDR

Cytoadhesion of infected red blood cells in Plasmodium falciparum malaria is mediated by variant surface antigens, with pregnancy‑associated malaria linked to PfEMP1‑mediated adhesion to chondroitin sulphate A in the placenta. The study focuses on the var2csa gene, a highly conserved var subfamily lacking CIDR and DBL‑γ domains that distinguishes it from other PfEMP1 variants. Selection for CSA adhesion in vitro and analysis of placental isolates revealed marked upregulation of var2csa, whose higher transcription in placental parasites supports its role as the adhesion molecule driving pregnancy‑associated malaria.

Abstract

Summary 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‐γ 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.