Molecular mechanisms of Chlamydia-induced Type 1 Interferon response

描述（由申请人提供）：沙眼衣原体是女性盆腔炎、异位妊娠和不孕症的主要原因。此外，由衣原体引起的眼沙眼仍然是世界上可预防失明的主要原因。衣原体感染是由t细胞介导的适应性免疫应答清除的，该应答依赖于初始的先天免疫应答。最近，I型干扰素（IFNs）在细菌感染过程中的重要作用被认识到。I型IFN反应主要通过激活病原体识别受体（PRR），如toll样受体（TLR）和其他细胞质PRR，如RIG-1， MDA5，识别与病原体相关的特定分子模式（PAMP）发生。我们已经观察到I型干扰素在增加细菌脱落和诱导阴道病理中的重要作用。本提案的总体目标是描述衣原体感染期间参与诱导I型ifn （IFNa/¿）的TLR/PRR途径。具体来说，我们将确定，1。在小鼠生殖道模型中，I型IFN促进感染和输卵管病理的机制，2。2 .确定衣原体感染过程中参与诱导IFNa/¿和干扰素反应基因（IRG）的TLRs/PRRs；3 .确定衣原体感染期间诱导IFNa/¿的下游信号事件；确定衣原体包涵体对宿主IFNa/¿反应产生的贡献以及细胞内TLR/PRR与衣原体的相互作用。

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.