Kemri-Wellcome Trust Research Programme: Functional studies of the malaria-protective Dantu polymorphism

Recent high throughput studies have identified multiple human genetic polymorphisms associated with strong protection against severe and complicated Plasmodium falciparum malaria. Most of these are found in or near genes that are important for the structure and function of red blood cells (RBCs), the primary host cell for P. falciparum parasites in humans. Of particular interest is a novel structural polymorphism in the glycophorin (GYP) locus, a GYPA and GYPB gene rearrangement resulting in a hybrid gene encoding the Dantu blood group. Dantu is found at highest frequency on the East African coast of Kenya. Given the important functional role of the GYP proteins in the invasion of P. falciparum parasites into RBCs, and the strong protective effect of Dantu against severe malaria, developing a full understanding of the protective mechanism might enable the development of new interventions that inhibit invasion. Over the last two years I have established that Dantu impedes parasite invasion by impacting the RBC biophysical properties. I propose to elucidate the molecular mechanisms through which this is achieved, how P. falciparum adapts to the changing RBC environment, and the wider health consequences of Dantu that have driven its selection in East Africa.

Programme: International Training Fellowship

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