Regulation of membrane fusion in macrophage phagocytosis

描述(申请人提供)：吞噬作用对于清除入侵的病原体、外来颗粒和死亡细胞体至关重要。这一过程的损害会导致疾病的发展，包括传染病。令人惊讶的是，尽管这一途径很重要，但有关吞噬小体成熟的控制机制(S)的信息有限。具体地说，控制内细胞室与吞噬小体融合的SNARE复合体的身份是不完整的。我们最近发现SNAP29蛋白在巨噬细胞杀死大肠杆菌的过程中起早期作用。基于这一发现，我们提出了一种假设，即SNAP29与早期的内吞陷阱形成融合复合体(ES)来控制吞噬小体成熟的早期步骤。使用一种独特的多学科方法，我们将识别和表征与大肠杆菌吞噬作用有关的含SNAP29的复合体。同时，我们将确定哪些早期的内吞陷阱在大肠杆菌吞噬过程中发挥作用，而不是与SNAP29有关。在此项目过程中收集的信息对于1)了解专业吞噬细胞(如巨噬细胞)如何清除细菌，2)确定细胞内细菌(如鼠伤寒沙门氏菌或结核分枝杆菌)可能危害以逃避杀戮的分子靶标，以及3)指导制定新的抗击传染病的策略是必要的。

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.