Mechanisms of Cytosolic Clearance of Rickettsiae

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Rickettsiae are intracellular bacteria that potentially cause life-threatening diseases all over the world. Rickettsiae possess the ability to invade host cells, quickly escape phagosomal vacuoles, and replicate in the cytoplasm. Autophagy targets cytoplasmic constituents in the autophagosomes and degrades them in the autolysosomes/lysosomes. Autophagy is now considered as a cornerstone of the intracellular surveillance system. The objective of the proposed project is to determine the interaction of rickettsiae with autophagy and its contribution to host control of fatal rickettsial diseases. We hypothesize that rickettsiae induce autophagy at the early stage of infection, which mediates degradation of cytosolic rickettsiae resulting in efficient host protective immunity of fatal rickettsial diseases. In the first Aim, we will determine whether autophagy is induced by rickettsiae and whether autophagy contributes to host control of fatal rickettsial diseases using a mouse model. In the second aim, we will identify how autophagy regulates the IL-1¿ response during fatal rickettsial diseases. The successful completion of the project will highlight the role of autophagy in host control of intracellular pathogens. The proposed project will provide important information on targeting autophagy for preventive and therapeutic interventions of fatal infectious diseases caused by intracellular microbes.