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、宫外孕和不孕症的主要原因。此外，衣原体引起的眼部沙眼仍然是世界上可预防的失明的主要原因。衣原体感染是通过T细胞介导的适应性免疫反应清除的，这种反应依赖于最初的先天免疫反应。最近，I型干扰素(IFN)在细菌感染中的重要作用被认识到，它是一种先天性反应。I型干扰素应答主要通过病原体识别受体(PRR)的激活而发生，如Toll样受体(TLR)和其他胞质PRR，如RIG-1，MDA5，它们识别与病原体相关的特定分子模式(PAMP)。我们观察到I型干扰素在毛滴虫感染过程中增加细菌脱落和引起输卵管病理的重要作用。这项建议的总体目标是描绘衣原体感染期间诱导I型IFN(IFNA/？)所涉及的TLR/PRR通路。具体地说，我们将确定，1.在小鼠生殖道模型中，I型干扰素促进感染和输卵管病理的机制；2.确定衣原体感染过程中诱导IFNA/？和干扰素反应基因(IRG)所涉及的TLRs/PRRs；3.确定衣原体感染过程中诱导IFNA/？的下游信号事件；4.确定衣原体包涵体在宿主IFNA/？应答产生中的作用以及细胞内TLR/PRR与衣原体的相互作用。 我们已经确定，在沙眼衣原体感染过程中诱导宿主I型IFN可能是衣原体实现较慢清除并增加其传播的一种机制。本研究探讨了I型干扰素如何在宿主体内诱导，延迟衣原体清除的基本机制。我们还将确定衣原体感染过程中干扰素诱导的细胞和分子机制(S)。这些研究对于了解衣原体的发病机制和免疫，并最终开发出针对这种病原体的疫苗至关重要。

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.