IRGM-driven host responses to Chlamydia trachomatis infections

描述(申请人提供)：沙眼衣原体是美国最常见的细菌性性传播疾病的病因。通常被称为一种无声的流行病，沙眼衣原体在女性中的感染通常是无症状的，经常被忽视和治疗。这种感染可以持续数年，慢性感染最终会导致盆腔炎、宫外孕和不孕症。尽管一些人成功地清除了沙眼衣原体感染，但另一些人却未能做到。个体清除沙眼衣原体感染的能力的异质性表明，对沙眼衣原体感染的相对抵抗力背后存在遗传成分。我们先前的无偏见遗传方法导致免疫相关GTPase(IRGS)被确定为宿主对沙眼衣原体感染抵抗的关键介质。IRGM蛋白是IRGS的一个亚家族，在小鼠和人类中都存在，而人的IRGM蛋白可以抵抗沙眼衣原体的感染。重要的是，人类IRGM基因座高度多态，与感染性和自身炎症性疾病的易感性增加有关。因此，IRGM基因座是决定沙眼衣原体感染结局的重要因素。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抵抗力。(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耐药途径。(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基因的遗传变体在提供对沙眼衣原体的细胞自主耐药能力方面是否存在差异。(3)我们将使用新的小鼠模型描述体内对沙眼衣原体的IRGM依赖的免疫反应。希望这些研究不仅能极大地促进我们对沙眼衣原体宿主反应的了解，而且有助于开发新的免疫学和药理学策略来预防沙眼衣原体的慢性感染。

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.