Regulation of membrane fusion in macrophage phagocytosis

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DESCRIPTION (provided by applicant): Phagocytosis is critical for the elimination of invading pathogens, foreign particles, and dead cell bodies. Impairment of this process results in the development of disease, including infectious diseases. Surprisingly, despite the importance of this pathway, limited information is available regarding the mechanism(s) controlling phagosome maturation. In particular, the identity of the SNARE complexes controlling the fusion of the endocytic compartments with the phagosomes is incomplete. We have recently identified that the SNARE protein SNAP29 plays an early role in the killing of Escherichia coli by macrophages. Based on this discovery, we propose to address the hypothesis that SNAP29 forms fusogenic complex(es) with early endocytic SNAREs to control the early step of phagosome maturation. Using a unique multi-disciplinary approach, we will identify and characterize SNAP29-containing complexes involved in E. coli phagocytosis. In parallel, we will identify which early endocytic SNAREs play a role in E. coli phagocytosis, regardless of being involved with SNAP29. The information gathered during the course of this project is necessary to 1) understand how professional phagocytic cells such as macrophages eliminate bacteria, 2) identify molecular targets that intracellular bacteria such as Salmonella typhimurium or Mycobacterium tuberculosis may compromise to escape killing, and 3) guide the development of new strategies to fight infectious diseases.