Malaria remains a global health threat, with over 250 million cases and 600,000 deaths annually. Before progressing to the blood stage, the malaria parasite develops asexually and asymptomatically in the liver. Although protein trafficking is critical for parasite proliferation in host hepatocytes, the mechanisms governing vesicle fusion during the liver stage of infection remain unclear. This study aims to elucidate how vesicle fusion is regulated during infection and how Plasmodium may exploit host vesicle-fusion machinery. One proposed mechanism involves hijacking host SNARE complexes, which mediate vesicle fusion with the target membrane. Previous research in our lab has shown that when vesicle-associated membrane protein 3 (VAMP3), a key regulator of endosomal recycling and membrane fusion, was knocked down, Plasmodium exhibited significant decreases in its load and size. Furthermore, VAMP3 is recruited to the parasite vacuole throughout liver-stage infection. We hypothesize that Plasmodium encodes its own SNARE proteins that form SNARE complexes with host VAMP3. To identify potential host-parasite SNARE interactions, we used AlphaFold 3 to model the three proteins required to form the SNARE complex. Models predicting strong protein-protein interactions between host and Plasmodium proteins were validated using co-immunoprecipitation assays. Using HA-magnetic beads, we successfully co-immunoprecipitated five overexpressed P. berghei SNARE proteins (PBANKA_0307600, PBANKA_1012900, PBANKA_1346800, PBANKA_1316200, and PBANKA_1418800) with endogenously tagged 2xV5- VAMP3. Current efforts focus on validating the localization of the Plasmodium protein to the parasitophorous vacuolar membrane (PVM), the host-parasite interface where nutrient exchange occurs. Together, these findings reveal a previously underexplored host-parasite interaction and suggest that targeting VAMP3 could be a promising approach to combat malaria. Symposium Presenter: Nimaye Garodia

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