Grant: Operating Grant

We aim to better understand the regulation of the immune system, which may aid in the development of novel strategies to mitigate infectious and/or autoimmune conditions. Macrophages and dendritic cells are white blood cells that search and engulf pathogens by a process called phagocytosis. After phagocytosis, pathogens are sequestered in a new organelle called the phagosome. While phagosomes are initially innocuous, they eventually fuse with lysosomes to become a phagolysosome, a highly acidic and degradative organelle. As a result, pathogens are killed and digested. Phagosome maturation also generates protein fragments (peptides) that are loaded onto the major histocompatibility complex-II (MHC-II). The peptide-MHCII complex is then transported to the surface of macrophages and dendritic cells for antigen presentation, which helps activate the immune system to generate antibodies. In resting macrophages and dendritic cells, lysosomes and the MHC-II compartment (MIIC), a lysosome-related organelle, are small and globular - however, upon exposure to bacterial compounds, lysosomes and the MIIC are converted into a tubular network, on which stunningly little is known. Importantly, MIIC and lysosome tubules are implicated in antigen presentation, phagosome maturation and retention of pinocytic uptake. This proposal describes pioneering research aimed at better understanding the function and biogenesis of tubular lysosomes and MIIC by: 1. Examining the molecular mechanisms responsible for lysosome tubulation in macrophages. 2. Dissecting the effect of tubulation on lysosome physiology. 3. Studying the molecular mechanisms of tubular MIIC formation and their role in MHC-II secretion and trafficking from phagosomes in dendritic cells. We expect this research to represent a major leap forward in the understanding of these poorly characterized organelles and that it may guide in the development of therapies against infectious and autoimmune conditions.