Molecular mechanisms of Chlamydia-induced Type 1 Interferon response

衣原体诱导 1 型干扰素反应的分子机制

• 批准号: 7425070
• 负责人: Uma M Nagarajan
• 金额: $ 31.56万
• 依托单位: ARKANSAS CHILDREN'S HOSPITAL RES INST
• 依托单位国家: 美国
• 财政年份: 2007
• 资助国家: 美国
• 起止时间: 2007-06-03 至 2012-05-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7425070
• 关键词: Address; Bacterial Infections; Binding; Blindness; CXCL10 gene; Cell physiology; Cells; Chlamydia; Chlamydia Infections; Chlamydia trachomatis; Dendritic Cells; Disease; Ectopic Pregnancy; Event; Generations; Genes; Genital system; IRF3 gene; Immune response; Immunity; In Vitro; Individual; Infection; Infertility; Inflammation; Interferon Type I; Interferon-alpha; Interferons; Mammalian Oviducts; Mediating; Modeling; Molecular; Mus; Nuclear Translocation; Nucleotides; Numbers; Pathogenesis; Pathology; Pathway interactions; Pattern; Pattern recognition receptor; Pelvic Inflammatory Disease; Play; Principal Investigator; Protein Family; Proteins; RNA Interference; Resolution; Role; Sampling; Shapes; Signal Pathway; Signal Transduction; T-Lymphocyte; TLR2 gene; TLR4 gene; TLR7 gene; Technology; Toll-like receptors; Trachoma; Vaccines; Viral; Wild Type Mouse; Woman; chemokine; cytokine; day; extracellular; gene induction; genital infection; macrophage; pathogen; programs; receptor; response; transcription factor; transmission process

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.

描述（由申请人提供）：沙眼衣原体是盆腔炎、宫外孕和女性不孕症的主要原因。此外，由衣原体引起的眼沙眼仍然是世界上可预防的失明的主要原因。衣原体感染通过依赖于初始先天免疫应答的T细胞介导的适应性免疫应答清除。最近，I型干扰素（IFN），一种先天性反应，在细菌感染过程中的重要作用正在被认识到。I型IFN应答主要通过激活病原体识别受体（PRR）（例如Toll样受体（TLR））和其它胞质PRR（例如RIG-1、MDA 5）而发生，其识别与病原体相关的特定分子模式（PAMP）。我们已经观察到I型干扰素在C.小鼠感染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。确定衣原体感染过程中参与诱导IFN α/γ和干扰素应答基因（IRG）的TLR/PRR。确定在衣原体感染期间诱导IFN α/γ的下游信号传导事件，和4.确定衣原体包涵体对产生宿主IFNa/γ应答的贡献以及细胞内TLR/PRR与衣原体的相互作用。 我们已经确定，诱导宿主I型干扰素在沙眼衣原体感染可能是一种机制，通过这种机制，衣原体可能会实现缓慢的清除，并增加其传播。本研究探讨了I型干扰素诱导宿主延迟衣原体清除的基本机制。我们还将确定衣原体感染期间IFN诱导的细胞和分子机制。这些研究对于了解衣原体的发病机制和免疫力，并最终开发针对该病原体的疫苗至关重要。