Plasmodium falciparum–Infected Erythrocytes: Agglutination by Diverse Kenyan Plasma Is Associated with Severe Disease and Young Host Age

Abstract

The variant surface antigens (VSAs) of Plasmodium falciparum-infected red blood cells are potentially important targets of naturally acquired immunity to malaria. Natural infections induce agglutinating antibodies specific to the VSA variants expressed by the infecting parasites. Previously, when different parasite isolates were tested against a panel of heterologous plasma from Kenyan children, the proportion of plasma that agglutinated the parasites (the agglutination frequency [AF]) was highly variable among isolates, suggesting the existence of rare and prevalent variants. Here, the AF of 115 isolates from Kenyan children were compared. The results show that the AF of isolates causing severe malaria were significantly higher than those of isolates causing mild malaria; and AF decreased significantly with the increasing age of the infected child. We propose that parasites causing severe disease tend to express a subset of VSA variants that are preferentially associated with infections of children with low immunity.

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

“…The main targets of these Abs are believed to be VSA expressed on the surface of IE (8,20,21). Previous publications suggest VSA-specific immune responses to impose a restriction on the repertoire of variant Ags compatible with parasite survival and to drive expression from VSA SM toward VSA UM during the early years of childhood (4,6,22). VSA SM appears to be serologically less diverse than VSA UM (7), consistent with the observation that immunity to severe malaria is acquired more rapidly than to uncomplicated disease and subclinical infection (23).…”

“…VSA severe malaria (VSA SM ) expressed by parasites, causing severe P. falciparum malaria in young children with no or little protective immunity, appear serologically more conserved than VSA (VSA uncomplicated malaria (VSA UM )) expressed by parasites causing uncomplicated and subclinical infection in older and more immune individuals (4,6). 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).…”

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.…”

“…However, some promising liver-and blood-stage candidate vaccine molecules have been selected after analysis of naturally acquired immune responses [30,31]. Also, the variant surface antigens (VSAs) of parasites that cause severe disease are different from and more immunogenic than those isolated from cases of mild malaria [32]. The possibility of exploiting this as a vaccine strategy is considered later.…”

Pathogenic mechanisms in Plasmodium falciparum malaria

“…Los estudios serológicos respaldan esta hipótesis; los parásitos que causan enfermedad grave en niños no inmunes tienden a expresar subtipos específicos de antígenos de superficie que se expresan con menor frecuencia en niños con cierto grado de inmunidad (31).…”