Seasonal variation in agglutination of Plasmodium falciparum-infected erythrocytes.

Abstract

Abstract. Agglutination and rosette formation are in vitro characteristics of Plasmodium falciparum-infected erythrocytes, which have been associated with host protective immune responses and also with parasite virulence. The present study was carried out in an area of seasonal and unstable malaria transmission in eastern Sudan. Plasma samples were obtained before, during, and after the transmission season from a volunteer cohort of 64 individuals seven years of age and older. These plasmas were assayed for their ability to agglutinate cultured parasitized erythrocytes originally obtained from acute malaria infection samples taken from five of the cohort members. Our data show that the capacity of donor plasma samples to agglutinate parasitized cells depended largely on the time of sampling relative to the transmission season, at least within this epidemiologic setting. Thus, although less than half of the pretransmission season samples could agglutinate any of the five lines of cultured parasites, all post-transmission season samples could agglutinate at least one of the parasite lines, with 74% agglutinating two or more lines. This increase in the agglutination capacity of individual plasma samples after the transmission season occurred essentially regardless of whether an individual had experienced a clinical malaria attack during the transmission season. The study thus confirms the acquisition of agglutinating antibodies following episodes of clinical malaria, but also demonstrates that such acquisition can take place in the absence of disease, presumably as a consequence of subclinical infection. This is the first demonstration of marked seasonal fluctuations in the capacity of individuals' sera to agglutinate parasitized red blood cells. Possible explanations for this effect include a decrease in the levels of agglutinating antibodies between seasons, or shifts in the antigens being recognized by such antibodies from one transmission season to the next. Finally, we showed the existence of marked seasonal fluctuation in the levels of agglutinating antibodies, either because levels of such antibodies are not sustained between seasons or because the antigens recognized change from one season to the next.Erythrocytes infected by Plasmodium falciparum express highly variable parasite-derived neoantigens at the red blood cell surface membrane during the later stages of their development. 1-3 Predominant among these antigens is PfEMP-1, an extremely polymorphic molecule encoded by the recently identified var gene family. [4][5][6] Antibodies responsible for agglutination (cross-linking) of P. falciparum-infected erythrocytes have been shown to specifically recognize variable antigens on the surface membrane of infected erythrocytes, 7, 8 and acquisition of protective immunity has been proposed to reflect the cumulative recognition of such antigens. 9 In line with this hypothesis, the ability of sera to agglutinate parasitized erythrocytes has been shown to correlate with relative protection of the serum donor fro...

The surface variant antigens of Plasmodium falciparum contain cross-reactive epitopes

“…As a consequence, antibodies induced by infection are clone-specific. This was shown clearly by acute and convalescent sera from children (1, 4, 6, 9), sera from experimentally infected Aotus monkeys (7), and sera from individuals living in areas of low or seasonal transmission (2,3,28). Even antibodies from malaria-immune African adults are variantspecific; the same antibodies only rarely will cross-agglutinate PEs from two variant clones (10).…”

“…For this mechanism to remain effective despite repeated exposure to P. falciparum, the response to PfEMP1 must be kept variant-specific. This is most likely done by diverting the immune response away from potential crossreactive determinants and directing it to strong, polymorphic, immunodominant epitopes (3,13,28). One such example is the CD36-binding fragment of CIDR1 that elicits antibodies by immunization in various animals but does not appear to elicit high-titer antibodies in humans or monkeys exposed to P. falciparum (refs.…”

Virulence in malaria: an evolutionary viewpoint

“…This variability is afforded by the multiple copies in the genome of their coding gene, denoted var (Baruch et al 1995;Smith et al 1995;Su et al 1995). These antigens are recognized by the immune system in a highly variantspecific way (Marsh & Howard 1986;Forsyth et al 1989;Newbold et al 1992;Iqbal et al 1993;Reeder et al 1994;Giha et al 1998;Bull et al 1999;Giha et al 1999;Nielsen et al 2002;Ofori et al 2002) although there appears to be some cross-reactivity between variants (Aguiar et al 1992;Chattopadhyay et al 2003). Low titres (Marsh et al 1989) and lack of recognition by antibody to the variant expressed by the infecting type has been associated with disease severity in field studies (Bull et al 1998(Bull et al , 2000Giha et al 2000;Nielsen et al 2002).…”

Low antibody responses to variant surface antigens of Plasmodium falciparum are associated with severe malaria and increased susceptibility to malaria attacks in Gabonese children.

“…16,[23][24][25] Numerous studies have demonstrated the wide diversity of VSA. 5,6,20,[26][27][28][29][30][31][32][33] Nevertheless, VSA do contain regions that are either identical or antigenically cross-reactive, and conserved epitopes are present in PfEMP-1. 34,35 More-recent studies have confirmed that VSA contain cross-reactive epitopes, lending support to the idea that these molecules could be used in the design of antiadhesive therapeutics.…”