T cell responses to PfEMP1

This research team investigates whether the phenotypic and antigenic properties of variant antigens expressed on the red cell surface of Plasmodium faciparum isolates determine cellular and humoral immune responses to that isolate.

Clinical immunity to Plasmodium falciparum bloodstage infection is related to exposure and to age, and occurs rapidly to severe disease, slower to mild disease and probably never to asymptomatic infection. However, at an age where children are most vulnerable to develop syndromes of severe disease, most children will harbour parasites but experience no or only mild clinical symptoms. The diversity of P. falciparum isolates is an important determinant of the heterogeneity in the phenotype of clinical malaria. Many targets of the humoral immune response are either polymorphic or undergo antigenic variation such as variant antigens expressed on the surface of infected red blood cells. Protective immune responses are associated with the ability to mount long-lived antibody responses to variant surface antigens expressed on "common" parasite isolates and the ability to mount to short-lived antibody responses during asymptomatic infection. However, in children with severe malaria, the relationship between parasite isolate, disease severity and host immune responses breaks down, suggesting that these children mount an inadequate antibody response. One family of variant proteins, the P. falciparum erythrocyte membrane protein-1 (PfEMP-1) mediates adhesion of bloodstage parasites to host cells and is central to both pathogenesis and protective immune responses. Cytoadhesion is an important determinant of organ-specific pathology in malaria but also results in the modulation of host cell function, both endothelial cells and dendritic cells. Adhesion of infected erythrocytes to CD36 modulates dendritic cell function in vitro and is positively correlated with the plasma concentration of IL-10 and inversely correlated with the plasma concentration of IL-12 in vivo. Dendritic cells initiate adaptive immune responses and control the deviation of T-cell responses. Therefore, the cytoadhesion phenotype of a given parasite isolate could influence the phenotype, duration and magnitude of adaptive T-cell and B-cell responses to that isolate.

Modern molecular typing techniques now permit to identify rapidly var genes encoding dominant expressed PfEMP-1 variants in a given isolate and allow for the first time to define cellular immune responses to that variant. We identify the dominant-expressed PfEMP-1 variants using a method developed by Dr. Pete Bull and express a small part of the first domain, the DBL-α tag as a recombinant protein in E. coli (James Tuju, Henry Karanje). The recombinant protein is used to determine the proportion of CD4+ T cells that secrete IFNγ, IL10 or both by flowcytometry in children with acute malaria and after convalescence (Evelyn Gitau, Eva Kimani). Ultimately, we want to define if and how the phenotypic and antigenic properties of a given parasite isolate shape the T-cell and B-cell responses that underlie the production of short-lived and long-lived antibodies against PfEMP-1.