Molecular mechanisms of Chlamydia-induced Type 1 Interferon response

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DESCRIPTION (provided by applicant): Chlamydia trachomatis is a major cause of pelvic inflammatory disease, ectopic pregnancy, and infertility among women. Further, ocular trachoma caused by chlamydiae continues to be the leading cause of preventable blindness in the world. Chlamydial infection is cleared by a T-cell-mediated adaptive immune response that depends on the initial innate immune response. Recently, the important role of type I interferons (IFNs), an innate response, during bacterial infection is being recognized. Type I IFN response occurs predominantly through activation of pathogen recognition receptors (PRR) such as Toll-like receptors (TLR) and other cytosolic PRR such as RIG-1, MDA5, that recognize specific molecular patterns associated with the pathogen (PAMP). We have observed an important role for type I IFNs in increasing bacterial shedding and inducing oviduct pathology during C. muridarum infection. The overall objective of this proposal is to delineate the TLR/PRR pathways involved in the induction of type I IFNs (IFNa/¿) during chlamydial infection. Specifically, we will determine, 1. The mechanism by which type I IFN promotes infection and oviduct pathology in the murine genital tract model, 2. Determine the TLRs/PRRs involved in the induction of IFNa/¿ and interferon response genes (IRG) during chlamydial infection, 3. Determine the downstream signaling events that induce IFNa/¿ during chlamydial infection, and 4. Determine the contribution of the chlamydial inclusion to generation of the host IFNa/¿ response and the interactions of intracellular TLR/PRR with Chlamydia. We have determined that induction of host type I IFNs during Chlamydia trachomatis infection could be a mechanism by which chlamydiae may achieve slower clearance and increase its transmission. The present study addresses the basic mechanisms of how type I IFNs induced in the host, delay chlamydial clearance. We will also determine the cellular and molecular mechanism(s) of IFN induction during chlamydial infection. These studies are essential to understand chlamydial pathogenesis and immunity, and eventually develop a vaccine against this pathogen.