IRGM-driven host responses to Chlamydia trachomatis infections

IRGM 驱动的宿主对沙眼衣原体感染的反应

• 批准号: 8826677
• 负责人: Joern Coers
• 金额: $ 39.25万
• 依托单位: DUKE UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2013
• 资助国家: 美国
• 起止时间: 2013-05-15 至 2016-04-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8826677
• 关键词: Alleles; Animals; Bacterial Sexually Transmitted Diseases; Binding; Binding Proteins; Biochemical; Biological; Blindness; Cell physiology; Cells; Chlamydia; Chlamydia trachomatis; Chronic; Data; Development; Disease; Ectopic Pregnancy; Epidemic; Epithelial Cells; Family; GTP Binding; Genes; Genetic; Genetic Polymorphism; Genetic Predisposition to Disease; Genetic Variation; Growth; Guanosine Triphosphate Phosphohydrolases; Health; Heterogeneity; Homologous Gene; Host resistance; Human; Immune; Immune response; Immunity; Individual; Infection; Infectious Agent; Infertility; Interferon Type II; Interferons; Knowledge; Mediator of activation protein; Membrane; Mus; Mycobacterium Infections; Names; Natural Immunity; Orthologous Gene; Outcome; Pathway interactions; Pelvic Inflammatory Disease; Play; Predisposition; Protein Family; Protein Isoforms; Proteins; Relative (related person); Resistance; Role; Shapes; Signal Transduction; Signaling Molecule; T-Lymphocyte; Testing; United States; Vaccines; Vacuole; Woman; Work; adaptive immunity; antimicrobial; design; genetic approach; genetic variant; guanylate; improved; in vivo; insight; member; mouse model; novel; novel therapeutics; paralogous gene; pathogen; prevent; resistance factors

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.

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。女性沙眼衣原体感染通常被称为无声流行病，通常无症状，并且经常被忽视和治疗。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。尽管有些人成功清除了沙眼衣原体感染，但其他人却未能成功。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存在遗传因素。我们之前的公正遗传方法导致免疫相关 GTP 酶 (IRG) 被鉴定为小鼠宿主抵抗沙眼衣原体感染的关键介质。 IRGM 蛋白是 IRG 的一个亚家族，存在于小鼠和人类中，人类 IRGM 可以提供对沙眼衣原体感染的抵抗力。重要的是，人类 IRGM 基因座具有高度多态性，并且与感染性和自身炎症性疾病的易感性增加有关。因此，IRGM 基因座很可能成为决定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抗性途径。 (2) 我们将定义哪些人类 IRGM 同种型负责提供对沙眼衣原体的抗性，以及人类 IRGM 基因的遗传变异体在提供对沙眼衣原体的细胞自主抗性的能力方面是否存在差异。 (3) 我们将使用新型小鼠模型描述体内对沙眼衣原体的 IRGM 依赖性免疫反应。希望这些研究不仅能够大大增进我们对宿主对沙眼衣原体反应的理解，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慢性感染。