Epidemiological and functional dissection of the co-evolution between Plasmodium falciparum parasites and sickle haemoglobin.

The "sickle" mutation (HbS; rs334 A>T) in the beta-globin gene (HBB) is the strongest known cause of natural resistance to Plasmodium falciparum malaria. While many mechanisms have been proposed to explain this protection, a recent paradigm-shifting study suggests that these should now be revisited. Through a large case-control study of severe malaria, we discovered that parasites could escape the protective effect of HbS if they carried mutations at specific P. falciparum sickle-associated (Pfsa) genetic loci. Such mutations are common in many African parasite populations, presumably due to HbS-driven natural selection, but the mechanisms by which they allow parasites to evade the protective effects of HbS remain completely unknown. We will discover these functional mechanisms by bringing together an interdisciplinary team of experts from Kenya and the UK to use epidemiological, population-genetic, multi-omic, parasite gene-editing and parasite phenotyping approaches to answer this fundamental question about host-pathogen co-evolution and human malaria resistance. Simultaneously, we will contribute to the development of science in Africa through shared leadership, the training of students, joint working, and technology transfer.