Host-ile take over: understanding how P. falciparum gametocytes subvert their host cell during infection

Gametocytes are the only stage of the malaria lifecycle that can be transmitted from humans to mosquitos to sustain disease transmission. Prior to being taken up by mosquitos, immature gametocytes sequester to the bone marrow where they extensively remodel the host cell in which they reside. For example, gametocytes can infect nucleated erythrocyte precursors, leading to a delay in erythroblast maturation. There is also evidence that parasite proteins exported onto the host cell surface are critical for mediating cell-cell interactions leading to the secretion of cytokines involved in angiogenesis, leading to remodelling of the bone marrow microenvironment. However, the parasite effectors responsible for these critical remodelling events remain to be identified. The aim of this proposal is to describe the mechanisms underlying the key remodelling events in gametocyte infected host cells and determine which parasite effector proteins are responsible for mediating them. Using state-of-the-art single-cell approaches, I will identify what erythroblast developmental pathways are perturbed upon gametocyte infection. I will also use a combination of reverse genetics and mass spectrometry to identify which effectors are responsible for host cell subversion and mediating cell-cell interactions. Overall, this work will identify key regulators of host cell remodelling required for malaria parasite transmission.