The Junction and beyond: molecular dissection of the first steps Apicomplexan parasites take to establish an intracellular niche

Plasmodium and Babesia ‘merozoites’ invade human red blood cells (RBCs) by forming a ‘moving junction’ (MJ): a molecular portal the merozoite deposits within the RBC membrane and drives itself through as entry progresses. Simultaneously, a parasitophorous vacuole membrane (PVM) forms around the invading merozoite, eventually enclosing and separating it from the RBC cytoplasm. However, whilst Plasmodium parasites remain within their PVM throughout development and modify it extensively for nutrient import/protein export, Babesia swiftly disrupt their PVM after invasion and replicate within the RBC cytoplasm instead. What causes these striking differences? I propose both MJ-mediated and post-invasion-mediated mechanisms underpin these distinct niche-forming strategies. Using a combination of reverse genetics, cutting-edge ‘live-cell to super-resolution’ imaging techniques, and spatial proteomics, I aim to dissect these mechanisms, focusing on i) novel/poorly understood roles of the MJ for host cell entry and PVM formation and ii) the roles of ‘rhoptry’ proteins secreted by the merozoite during/just after entry in facilitating PVM expansion (Plasmodium) or dissolution (Babesia). Overall, this comparative biology approach will give mechanistic insight into a universal Apicomplexan target of therapeutic value and help us understand how and why these parasites rapidly remodel their intracellular homes.