Immunity to Plasmodium falciparum: Could cross-reactive CD4+ T cell responses to PfEMP1 form the basis of an anti-disease malaria vaccine?

The diversity of Plasmodium falciparum isolates is an important determinant ofthe heterogeneity in clinical malaria. Many targets of the humoral immune response are polymorphic or undergo antigenic variation. Clinical immunity maybe the result of cumulative acquisition of a diverse antibody repertoire. Antibody responses to a variety of malarial antigens are short-lived and detectable only during asymptomatic infection.

However, the cellular mechanisms determining the nature of antibody responses in P. falciparum infection are not understood. One family of variant proteins, the P. falciparum erythrocyte membrane protein-1 (PfEMP-1) mediates adhesion of bloodstage parasites to host cells. Cytoadhesion is associated with (i) pathology, (ii) immune selection, and (iii) immune deviation.

I have shown that cytoadhesion of parasites to CD36 modulates dendritic cell function in vitro and systemic cytokine responses in vivo. I now propose to determine the relationship between the phenotype of parasite isolates and the immune responses to PfEMP-1 and how this relationship evolves with exposure. I will define: (i) Whether there are differences in cellular immune responses to PfEMP-1 dependent on the adhesion phenotype of the parasite isolate. (ii) The cellular mechanisms underlying the evolution of unique and cross-reactive antibody responses to PfEMP-1 during the natural history of infection.

May 2012 — Apr 2014

$861,812