Phagocytosis of foreign microorganisms by macrophages is a critical event in the initial response of the immune system to infection. Phagocytosis is a complex process that involves the sequential envelopment, internalization, and intracellular degradation of the invading organism within a membrane-enclosed phagosome. In order for macrophages to enclose extracellular objects, they must first form structures known as pseudopodia, extensions of the plasma membrane that can engulf a foreign object. Pseudopod formation is driven by both the intracellular production of membrane vesicles that fuse with the cell membrane to increase its surface area, as well as the polymerization of an underlying cytoskeletal substructure that supports the pseudopod. The goal of this project is to test the role of protein called dynamin as a master regulator of the early events of phagocytosis. Previous work has shown that dynamin is essential for phagocytosis. This project will define the role of dynamin in phagocytosis by determining (a) the location and behavior of dynamin during the internalization of foreign objects, (b) the structural features of dynamin that are important for its function and (c) the signaling pathway responsible for dynamin activation. A wide range of electrophysiological, biochemical and molecular tools will be used.
Phagocytic cells such as macrophages represent an organism's first line of defense against infectious microorganisms, yet our knowledge of the fundamental processes involved in phagocytosis is still sketchy. Indeed, many pathogenic bacterial and viral species have evolved mechanisms to subvert the normal phagocytic process. With a better understanding of the molecular mechanisms underlying the phagocytic process, it will be possible to design strategies to block the ability of microorganisms to circumvent their internalization and destruction.
