Cellular dissection of Plasmodium falciparum erythrocyte invasion (360G-Wellcome-220266_Z_20_Z)

Plasmodium falciparum parasites still cause nearly half a million deaths each year. The repeated emergence of antimalarial drug resistance and the lack of a highly effective vaccine mean that there is an urgent need to identify new intervention targets. Erythrocyte invasion is an excellent target as it is essential for both parasite survival and for malaria pathology. Invasion involves multiple parasite ligands, but little is known about their function at the cellular level and even less about how they fit into the broader network of invasion proteins. This proposal will revolutionise our understanding of the function of two families of P. falciparum invasion ligands, the EBLs and the RHs, that are together responsible for the key decision point in the invasion process. The key goals are to: Systematically dissect functional equivalence between EBLs and RHs Establish the roles that EBLs and RHs play in discriminating between erythrocyte variants within and between humans Use innovative combinatorial approaches to move from a gene to a network understanding of EBL and RH function. The proposal will provide a step change for the field, both biologically and technically, and will identify new candidates for testing in a rationally designed, multi-component invasion-blocking vaccine.