Elucidating the cellular mechanisms by which peroxisomes regulates phagocytosis in innate immune cells

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Organisms require an effective and tightly controlled defense system (immune system) to fight infections. Failures of the immune system affect every organism's survival. An organism's metabolic system is now recognized as an important mediator of proper immune responses. Peroxisomes are structures within cells that regulate important processes, notably lipid metabolism and the detoxification of reactive species. Studies in isolated mammalian and yeast cells suggest that peroxisomes act as important cellular "switch" that regulate specific functions in different cell type of the organisms. My recent work identified a previously unknown requirement for peroxisomes in activating the first line of defence against bacteria and infection (innate immune defence) in the fruit fly (Drosophila melanogaster). Fruit flies are commonly used in the laboratory to study basic cellular processes that are required for animal physiology. There is over one hundred years of scientific history where fruit flies have been used to understand how the different cells and tissue in the organisms develop and function, including the cells of the innate immune defense. We identified peroxisomes as essential mediators of the immune responses and particularly we described their requirement in engulfing pathogens (phagocytosis) in specialized cells (known as plasmatocytes in insects and macrophages in mammals) that defend our body from pathogens. Plasmatocytes and macrophages with inactive peroxisomes are unable to eliminate the pathogens. The next step in our basic understanding of the essential role of peroxisome in an organism's immune defense is to understand how peroxisomes "turn on and off" the immune defense. Our research will address two critical questions: 1) How peroxisomes affect the mechanisms of defense against pathogens in macrophages 2) What are the other "players"(cellular signaling) that regulate peroxisome-dependent phagocytosis in macrophages? 3) 1) How changes in peroxisome metabolism affects phagocytosis and other immune responses. The proposed research will lead to 1) training of Highly Qualified Personnel in cutting-edge research and transferable skills for diverse careers; and 2) important scientific contributions to the innate immune response and makes a core addition to the roles of peroxisomes in animal physiology. .