Evidence for the Involvement of VAR2CSA in Pregnancy-associated Malaria

TLDR

In Plasmodium falciparum–endemic regions, pregnancy‑associated malaria arises from placental sequestration of infected erythrocytes that bind chondroitin sulfate A via parasite‑encoded variant surface antigens, with VSAPAM antibodies being sex‑specific and parity‑dependent. We demonstrate that VAR2CSA is displayed on CSA‑selected infected erythrocytes, is recognized by endemic plasma in a sex‑specific and parity‑dependent fashion, and that high anti‑VAR2CSA IgG levels in pregnant women correlate with heavier newborns and a reduced risk of low birth weight.

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, 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.