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。沙眼衣原体感染通常被称为无声的流行病，妇女感染沙眼衣原体通常无症状，经常不被注意和治疗。感染可持续数年，慢性感染最终导致盆腔炎、异位妊娠和不孕症。有些人能成功清除沙眼衣原体感染，有些人则不能。个体清除沙眼衣原体感染能力的异质性表明，对沙眼衣原体感染的相对抗性存在遗传成分。我们之前的无偏遗传方法鉴定了免疫相关GTPase （IRGs）作为宿主对小鼠沙眼衣原体感染抗性的关键介质。IRGM蛋白是IRGs的一个亚家族，在小鼠和人类中都存在，并且人类IRGM可以提供对沙眼衣原体感染的抗性。重要的是，人类IRGM基因座是高度多态性的，并且与对感染性和自身炎症性疾病的易感性增加有关。因此，IRGM基因座是形成沙眼衣原体感染结果的关键决定因素。我们正在追求三个相互关联的目标，以了解IRGM蛋白如何在小鼠和人类中提供对沙眼衣原体感染的抗性。(1)我们将确定IRGM蛋白如何协调针对沙眼衣原体的细胞自主抗性途径(2)我们将确定哪些人类IRGM亚型负责提供对沙眼衣原体的抗性，以及人类IRGM基因的遗传变异是否在提供对沙眼衣原体的细胞自主抗性的能力上存在差异。(3)我们将利用新型小鼠模型描述irgm依赖的沙眼衣原体免疫反应。希望这些研究不仅将大大提高我们对沙眼原体宿主反应的理解，而且有助于开发新的免疫和药理学策略来预防沙眼原体的慢性感染。

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.