Evidence for the Involvement of VAR2CSA in Pregnancy-associated Malaria

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.

3D7-Derived Plasmodium falciparum Erythrocyte Membrane Protein 1 Is a Frequent Target of Naturally Acquired Antibodies Recognizing Protein Domains in a Particular Pattern Independent of Malaria Transmission Intensity

“…Using 20 different 3D7-derived rPfEMP1 domains representing all the different ups types in 3D7 (10), except the upsE VAR2CSA associated with pregnancy malaria (14) (Table I), we compared IgG levels in plasma from individuals aged 2-19 years, living under high (Mgome), moderate (Ubiri), and low (Magamba) malaria transmission intensity (Fig. 1).…”

“…a The domains represented all the different ups types in 3D7 (10), except upsE, which is found upstream of var2csa associated with pregnancy malaria (14). distinct sequence classes (12).…”

“…A total of 20 different r3D7 protein domains representing PfEMP1 domains of all the different ups types in 3D7 (10), except upsE found upstream of VAR2CSA associated with pregnancy associated malaria (14), were cloned and expressed for ELISA. Slightly more upsA-type domains compared with other ups types were included in the study because previous studies had implied that Abs against these domain would be acquired early in life and that parasites expressing at least some of these domains would be virulent (13).…”

Towards an anti-disease malaria vaccine

“…Here, a single PfEMP1 in each parasite genome, known as VAR2CSA, was specifically expressed in parasites isolated from pregnant women suffering from malaria [26,27]. VAR2CSA mediates the sequestration of infected erythrocytes by binding to the chondroitin sulphates that fill the spaces of the placenta in contact with maternal blood [26,28].…”

“…Here, a single PfEMP1 in each parasite genome, known as VAR2CSA, was specifically expressed in parasites isolated from pregnant women suffering from malaria [26,27]. VAR2CSA mediates the sequestration of infected erythrocytes by binding to the chondroitin sulphates that fill the spaces of the placenta in contact with maternal blood [26,28]. With just one PfEMP1 associated with this form of the disease, and with immunity to pregnancy-associated malaria in multigravid women being associated with antibodies that bind VAR2CSA [29], this is a promising vaccine candidate and is being tested in clinical trials [30].…”