Plasmodium falciparum Associated with Severe Childhood Malaria Preferentially Expresses PfEMP1 Encoded by Group A var Genes

Abstract

Parasite-encoded variant surface antigens (VSAs) like the var gene–encoded Plasmodium falciparum erythrocyte membrane protein 1 (PfEMP1) family are responsible for antigenic variation and infected red blood cell (RBC) cytoadhesion in P. falciparum malaria. Parasites causing severe malaria in nonimmune patients tend to express a restricted subset of VSA (VSASM) that differs from VSA associated with uncomplicated malaria and asymptomatic infection (VSAUM). We compared var gene transcription in unselected P. falciparum clone 3D7 expressing VSAUM to in vitro–selected sublines expressing VSASM to identify PfEMP1 responsible for the VSASM phenotype. Expression of VSASM was accompanied by up-regulation of Group A var genes. The most prominently up-regulated Group A gene (PFD1235w/MAL7P1.1) was translated into a protein expressed on the infected RBC surface. The proteins encoded by Group A var genes, such as PFD1235w/MAL7P1.1, appear to be involved in the pathogenesis of severe disease and are thus attractive candidates for a vaccine against life-threatening P. falciparum malaria.

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 Ab-selected and nonselected 3D7 sublines, we have previously established a link between expression of groups A and B/A PfEMP1 and a VSA SM phenotype and between expression of groups B, B/C, or C PfEMP1 and a VSA UM phenotype (13). Altogether, these findings imply that groups A and B/A PfEMP1 molecules are more frequently and better recognized by Abs acquired after natural infection than groups B, B/C, and C PfEMP1.…”

“…Using Ab-selected and nonselected 3D7 sublines, we have previously established a link between expression of groups A and B/A PfEMP1 and a VSA SM phenotype and between expression of groups B, B/C, or C PfEMP1 and a VSA UM phenotype. In particular, we have proposed a relationship between a VSA SM phenotype and expression of a 3D7 group A var encoded PfEMP1 PFD1235w/MAL8P1.207 (13). This proposed relationship implies the product of this gene to be recognized at high levels and early in life of individuals living in malaria endemic areas.…”

“…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). Domains and subtypes of DBL (␣, ␤, ␥, ␦, ), C2, and CIDR (␣, ␥) were defined as described in Ref.…”

“…GTS-tagged protein was purified as described above. His-tagged protein was purified from culture supernatants on a Co 2ϩ metal-chelate agarose column as described previously (13).…”

Malaria vaccines 1985–2005: a full circle?

“…The best-characterized variant is VAR2CSA, which is sex specific and highly transcribed [39,40]. Also, as we have seen, the variant proteins from parasites that cause severe malaria in non-immune patients differ from those expressed by parasites that cause uncomplicated malaria [32,41]. Targeting these small groups of variants offers the intriguing possibility of developing vaccines specifically to protect women in pregnancy and the children most at risk of severe disease.…”