Rapid switching to multiple antigenic and adhesive phenotypes in malaria

Abstract

Adhesion of parasitized erythrocytes to post-capillary venular endothelium or uninfected red cells is strongly implicated in the pathogenesis of severe Plasmodium falciparum malaria. Neoantigens at the infected red-cell surface adhere to a variety of host receptors, demonstrate serological diversity in field isolates and may also be a target of the host-protective immune response. Here we use sequential cloning of P. falciparum by micromanipulation to investigate the ability of a parasite to switch antigenic and cytoadherence phenotypes. Our data show that antigens at the parasitized cell surface undergo clonal variation in vitro in the absence of immune pressure at the rate of 2% per generation with concomitant modulations of the adhesive phenotype. A clone has the potential to switch at high frequency to a variety of antigenic and adhesive phenotypes, including a new type of cytoadherence behaviour, 'auto-agglutination' of infected erythrocytes. This rapid appearance of antigenic and functional heterogeneity has important implications for pathogenesis and acquired immunity.

Virulence in malaria: an evolutionary viewpoint

“…All three properties have been implicated as virulence factors in human malaria Langreth & Peterson 1985;MacPherson et al 1985;Carlson et al 1990;Rowe et al 1995;Roberts et al 2000;Pain et al 2001). Finally, both species provoke strain-specific immunity (Taliaferro 1949;Jeffery 1966;Jarra & Brown 1985;Snounou et al 1989;Mota et al 1998), and both species undergo clonal antigenic variation (McLean et al 1982;Biggs et al 1991;Roberts et al 1992). However, there are some marked differences between P. falciparum in the field and P. chabaudi in laboratory mice.…”

“…Like cytoadherence, perhaps the most compelling evidence that antigenic variation confers a fitness advantage is its prevalence throughout the Plasmodium genus. Evidence for antigenic variation exists in all species of parasite studied (P. berghei (Cox 1962); P. knowlesi (Brown & Brown 1965); P. cynomolgi (Voller & Rossan 1969); P. falciparum Biggs et al 1991;Roberts et al 1992); P. chabaudi (McLean et al 1982); P. fragile (Handunetti et al 1987); and probably P. vivax del Portillo et al 2001)). Different sets of genes are responsible in different species (Howard & Barnwell 1985;al-Khedery et al 1999;del Portillo et al 2001;Janssen et al 2001Janssen et al , 2002, suggesting convergent evolution for this phenotype.…”

Parasite antigens on the infected red cell surface are targets for naturally acquired immunity to malaria

“…family of target antigens, because these proteins are inserted into the red cell surface and are prominently exposed [4][5][6] and because they are highly polymorphic and undergo clonal antigenic variation 7,8,18 , a mechanism of immune evasion maintained by a large family of var genes [9][10][11] . In a large prospective study of Kenyan children, we have used the fact that anti-PfEMP1 antibodies agglutinate infected erythrocytes in a variant-specific manner 10,[12][13][14][15][16] , to show that the PfEMP1 variants expressed during episodes of clinical malaria were less likely to be recognized by the corresponding child's own preexisting antibody response than by that of children of the same age from the same community.…”

Pathogenic mechanisms in Plasmodium falciparum malaria

“…La PfEMP1 se adhiere a todos los receptores identificados; es una proteína polimorfa de alto peso molecular (200-350 kDa), con tasas de variación antigénica clonal in vitro de 2 % por ciclo de vida (24,25). Esta proteína es codificada por la familia multigénica var, localizada preferencialmente en los subtelómeros de los cromosomas, donde se favorece la recombinación para generar diversidad.…”