Unraveling the Molecular Mechanisms of Phagocytosis(RMI)

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Phagocytosis is a special form of endocytosis in which large particles such as microorganisms and dead cells are ingested via large endocytic vesicles called phagosomes. In mammals, three classes of white blood cells act as professional phagocytes: macrophages, neutrophils and dendritic cells. These cells defend us against infection by ingesting invading pathogens. Macrophages have also an important role in scavenging senescent cells and cells that have died by apoptosis. In quantitative terms, the scavenging dead cells are by far the most important: our macrophages phagocytose more than 1011 senescent red blood cells in each of us every day, for example. Although multiple cellular elements are known to be involved in phagocytosis, the regulation of this pathway is still obscure. For example, it is unclear which membranes are recruited for the formation of the phagosome and under which conditions each compartment is mobilized. It is also unclear which proteins are involved in the process (in particular the fusion proteins). In this application, we seek to address these questions. By using a cell assay based on fluorescent latex beads, we will investigate 1- which compounds are influencing the internalization of different size particles and 2- which regulatory elements are involved. Understanding the molecular mechanism of phagosome formation and maturation is fundamental for the discovery of new drug targets and the development of new treatments for a wide variety of infectious diseases. The leading re-emerging infectious disease is tuberculosis caused by mycobacterium tuberculosis (and to much lesser extent mycobacterium bovis). M. tuberculosis is one of several pathogens that exploit host cell phagocytic machinery to gain access to the cell interior and to escape immune surveillance.

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