Interactions between parasite surface antigens and host responses to Plasmodium falciparum and P. vivax

The parasite Plasmodium (P.) has co-evolved exquisitely with its human host over thousands of years. Six species infect humans and over two hundred other species infect animals including reptiles, birds and mammals. The effects of Plasmodium on these hosts vary from benign to lethal infections, depending on the virulence of the parasite and the ability of the host to respond to infection. In humans, P. falciparum causes significant pathogenesis, while other species such as P. vivax appear less virulent with lower parasitemia and fewer pathogenetic effects on the host.
The expression of surface proteins on the infected red blood cell highlights a key immune evasion strategy evolved by P. falciparum. These proteins mediate cellular adhesion through interaction with specific ligands on human epithelial cells. The surface proteins are encoded by the ‘var’ gene family, which consists of approximately 60 genes in the P. falciparum genome. Expression of var genes is controlled by a genetic mechanism of allelic exclusion whereby parasites switch expression to a different var gene with each generation and presents a different surface antigen that is new to the immune system.

Immunity is gradually acquired upon exposure to multiple surface variants. An important exception is in pregnancy where antibodies fail to recognize a particular VAR protein, PfVAR2CSA, which mediates cytoadherence in the placenta. Based on studies in Africa, the current view is that the expression of var2csa is silenced except in placental parasites, and antibodies are only measured in pregnant women after exposure to placental infection. However, this view was challenged with some startling observations from Colombia: 1) high levels of antibodies to PfVAR2CSA was measured in men and children, and 2) Men, women and children exposed only to P. vivax had antibodies to this P. falciparum protein. These findings present a biological puzzle that needs to be unravelled in the proposed research program. An important clue may be that in Africa, P. falciparum is the predominant species whereas in Colombia, both P. falciparum and P. vivax co-evolved. We propose that this geographical overlap led to evolutionary changes in parasites that altered their mechanisms of immune evasion. Building on the expertise in basic cell biology and genetics, my research program will investigate the genetic control of var gene expression, characterize the DNA sequences and perform phylogenetic analyses of Colombian isolates, identify sequences that define the cross-reactivity of antibodies between P. falciparum and P. vivax and map these epitopes, and test for adhesion of these antibodies to specific ligands in parasite cultures and in vivo.

Project Details

Basic Science
Immunology
P. vivax

Apr 2015 — Mar 2016

$23,474

Canada