IRGM-driven host responses to Chlamydia trachomatis infections

描述（由申请人提供）：沙眼衣原体是美国最常见的细菌性传播疾病的病因。通常被称为沉默的流行病，C。妇女的沙眼感染通常没有症状，常常不被注意和治疗。感染可以持续数年，慢性感染最终导致盆腔炎，异位妊娠和不孕症。而有些人清除了C。沙眼患者成功，其他人则失败。个体清除C.沙眼衣原体感染提示对沙眼衣原体相对耐药的遗传因素。沙眼感染我们先前的无偏遗传学方法导致免疫相关GT3（IRGs）作为宿主对C耐药的关键介质的鉴定。小鼠沙眼感染。IRGM蛋白是IRG的一个亚家族，在小鼠和人类中都存在，并且人类IRGM可以提供对C.沙眼感染重要的是，人IRGM基因座是高度多态性的，并且与感染性和自身炎性疾病的易感性增加相关。因此，IRGM基因座是一个强有力的候选人，是一个关键的决定因素，在塑造C。沙眼感染我们正在追求三个相互关联的目标，以了解IRGM蛋白如何提供对C的抗性。小鼠和人类的沙眼感染。(1)我们将确定IRGM蛋白如何协调靶向C的细胞自主抗性途径。（2）我们将确定哪些人IRGM亚型负责提供对沙眼衣原体的抗性。以及人类IRGM基因的遗传变异体是否在提供细胞自主抵抗沙眼衣原体的能力方面存在差异。沙眼(3)我们将描述IRGM依赖的免疫反应，以C。使用新的小鼠模型在体内研究沙眼。希望这些研究不仅能大大促进我们对宿主对C.沙眼衣原体的研究，而且还促进了新的免疫学和药理学策略的发展，以防止慢性感染沙眼衣原体。沙眼

DESCRIPTION (provided by applicant): Chlamydia trachomatis is the cause for the most common bacterial sexually transmitted disease in the United States. Commonly referred to as a silent epidemic, C. trachomatis infections in women are frequently asymptomatic, and often go unnoticed and untreated. The infection can persist for years and chronic infections ultimately result in pelvic inflammatory disease, ectopic pregnancies, and infertility. Whereas some individuals clear infections with C. trachomatis successfully, others fail to do so. The heterogeneity in the ability of individuals to clear C. trachomatis infections suggests a genetic component underlying the relative resistance to C. trachomatis infections. Our previous unbiased genetic approach led to the identification of Immunity Related GTPase (IRGs) as critical mediators of host resistance to C. trachomatis infections in mice. IRGM proteins, a subfamily of IRGs, exist both in mice and humans and human IRGM can provide resistance to C. trachomatis infections. Importantly, the human IRGM locus is highly polymorphic and has been associated with increased susceptibility to infectious and autoinflammatory diseases. Therefore, the IRGM locus is a strong candidate to be a critical determinant in shaping the outcome of C. trachomatis infections. We are pursuing three interrelated aims to understand how IRGM proteins provide resistance to C. trachomatis infections in mice and humans. (1) We will determine how IRGM proteins orchestrate cell-autonomous resistance pathways targeting C. trachomatis (2) We will define which human IRGM isoforms are responsible for providing resistance to C. trachomatis and whether genetic variants of the human IRGM gene differ in their ability to provide cell-autonomous resistance to C. trachomatis. (3) We will describe IRGM-dependent immune response to C. trachomatis in vivo using novel mouse models. It is hoped that these studies will not only substantially advance our understanding of host responses to C. trachomatis but also facilitate the development of novel immunological and pharmacological strategies to prevent chronic infections with C. trachomatis.