Plasmodium falciparum Variant Surface Antigen Expression Varies Between Isolates Causing Severe and Nonsevere Malaria and Is Modified by Acquired Immunity

Abstract

In areas of endemic parasite transmission, protective immunity to Plasmodium falciparum malaria is acquired over several years with numerous disease episodes. Acquisition of Abs to parasite-encoded variant surface Ags (VSA) on the infected erythrocyte membrane is important in the development of immunity, as disease-causing parasites appear to be those not controlled by preexisting VSA-specific Abs. In this work we report that VSA expressed by parasites from young Ghanaian children with P. falciparum malaria were commonly and strongly recognized by plasma Abs from healthy children in the same area, whereas recognition of VSA expressed by parasites from older children was weaker and less frequent. Independent of this, parasites isolated from children with severe malaria (cerebral malaria and severe anemia) were better recognized by VSA-specific plasma Abs than parasites obtained from children with nonsevere disease. This was not due to a higher infection multiplicity in younger patients or in patients with severe disease. Our data suggest that acquisition of VSA-specific Ab responses gradually restricts the VSA repertoire that is compatible with parasite survival in the semi-immune host. This appears to limit the risk of severe disease by discriminating against the expression of VSA likely to cause life-threatening complications, such as cerebral malaria and severe anemia. Such VSA seem to be preferred by parasites infecting a nonimmune host, suggesting that VSA expression and switching are not random, and that the VSA expression pattern is modulated by immunity. This opens the possibility of developing morbidity-reducing vaccines targeting a limited subset of common and particularly virulent VSA.

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).…”

Plasmodium berghei sporozoite challenge of vaccinated BALB/c mice leads to the induction of humoral immunity and improved function of CD8+ memory T cells

“…People in endemic areas develop after repeated infections a nonsterile immunity against malaria [2] that is supposed to be based on antibodies against blood-stage antigens and IFN-γ made by CD4 + T cells [5,6]. Antibodies to sporozoites are also present in people living in endemic areas but at very low titers and after years of repeated exposure [37].…”

“…In contrast, the acquisition of anti-parasite immunity takes years to decades, although transmigrant studies show that adults may acquire immunity more rapidly than children [3,4]. It is supposed that anti-parasite immunity is based mainly on antibodies recognising variant surface antigens on the membranes of infected erythrocytes whereas immune responses against preerythrocytic forms seem to play a minor role [5,6]. Naturally acquired immunity is never sterile but enables adults in endemic areas to be infected without clinical symptoms and with low parasite densities.…”

“…With regard to our results one explanation could be that anti-sporozoite antibodies support the maintenance of CSP-specific memory T cells but also facilitate the activation of these memory T cells in case of reinfection with Plasmodium sporozoites. This issue needs to be further investigated.People in endemic areas develop after repeated infections a nonsterile immunity against malaria [2] that is supposed to be based on antibodies against blood-stage antigens and IFN-γ made by CD4 + T cells [5,6]. Antibodies to sporozoites are also present in people living in endemic areas but at very low titers and after years of repeated exposure [37].…”