Malaria parasite determinants of host cell tropism

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PROJECT SUMMARY Malaria continues to be a major scourge of humanity, and is caused by infection of red blood cells (RBCs) by the protozoan Plasmodium spp. parasites. Plasmodium falciparum can achieve high parasite biomasses in the circulation causing severe morbidity and mortality. Blood-stage parasites have a strict cellular tropism for RBCs, interacting with numerous molecular determinants in the RBCs for productive infection and transmission. Parasite polymorphisms that allow parasites to propagate and persist in different types of RBCs present a major challenge to malaria control and elimination. This includes the ability of the invasive merozoite forms to use different receptors on RBCs, known as invasion pathways. We will leverage the power of forward genetics to identify the molecular determinants mediating two key features of the cellular tropism of P. falciparum: RBC age and RBC species preference. We have found that different P. falciparum strains vary significantly in these preferences, and hypothesize that the parasite polymorphisms underlying this variation are critical to the emergence and persistence of P. falciparum in human populations, and are key determinants of pathogenesis and transmission. We will employ a forward genetics approach to identify polymorphisms and genes associated with RBC age and species preference, specifically Bulk Segregant Analysis (BSA) of progeny from genetic crosses of P. falciparum parental lines with varying invasion preferences. Reverse genetics approaches will be used for the functional analysis of naturally occurring polymorphisms in candidate genes, both singly and in combination. Together these studies will provide a comprehensive understanding of the molecular basis of cellular tropism in P. falciparum parasites, focused on RBC age and species preference. In the long-term we hope that our studies will elucidate the critical interactions required for the persistence, pathogenicity and transmission of P. falciparum in parasite populations, to inform public health interventions and inform vaccine development.