Interferon-inducible cell-intrinsic host defense against Chlamydia trachomatis

干扰素诱导的细胞内在宿主针对沙眼衣原体的防御

• 批准号: 10088369
• 负责人: Joern Coers
• 金额: $ 45.78万
• 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 2024-01-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10088369
• 关键词: Adaptive Immune System; Anti-Bacterial Agents; Bacterial Infections; Binding Proteins; Cell Culture System; Cells; Chemicals; Chlamydia; Chlamydia Infections; Chlamydia muridarum; Chlamydia trachomatis; Development; Disease; Dynamin; Ectopic Pregnancy; Endometrial; Epidemic; Epithelial Cells; Failure; Family; Female infertility; Functional disorder; Genes; Genetic Screening; Genomics; Goals; Growth; Guanosine Triphosphate Phosphohydrolases; Helper-Inducer T-Lymphocyte; Host Defense; Host resistance; Human; Immune; Immune response; Immune system; Immunity; Infection; Infertility; Inflammasome; Inflammation; Inflammatory; Interferon Type II; Interferons; Knowledge; Lead; Libraries; Life; Link; Lymphocyte; Mediating; Modeling; Monitor; Mus; Mutate; Mutation; Natural Immunity; Neutrophil Activation; Neutrophil Infiltration; Organoids; Pathogenesis; Pathway interactions; Pelvic Inflammatory Disease; Phenotype; Prophylactic treatment; Proteins; Regulation; Research; Resistance; Rodent; Role; Sexually Transmitted Diseases; Signal Transduction; Structure; T-Lymphocyte; Therapeutic; Therapeutic Intervention; United States; Vaccine Design; Vaccines; Vacuole; Virulence Factors; Woman; Work; adaptive immunity; bacterial genetics; chronic infection; cytokine; design; functional genomics; gain of function; gene function; guanylate; immunopathology; improved; in vivo; insight; interdisciplinary approach; loss of function; member; mouse model; mutant; mycobacterial; nonsynonymous mutation; novel; novel therapeutics; overexpression; pathogen; pathogenic bacteria; programs; prophylactic; receptor; recruit; resistance factors; response; sensor; therapy design

Chlamydia trachomatis is the cause for the most common bacterial sexually transmitted infection 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 months or years and ultimately cause pelvic inflammatory disease, ectopic pregnancies, and infertility. In order to establish persistent infections, C. trachomatis must subvert both the innate and the adaptive branches of the immune system. A central node that connects adaptive and innate immunity to C. trachomatis is the cytokine gamma-interferon (IFNγ). This cytokine is produced by lymphocytes such as T cells of the adaptive immune system and induces cell-intrinsic, innate host defenses against Chlamydia in epithelial cells. In order to overcome IFNγ-mediated immunity and replicate inside human epithelial cells, C. trachomatis evolved counterdefenses specifically adapted to its human host. These C. trachomatis counterdefenses and the corresponding repertoire of IFNγ-inducible anti-Chlamydia defense programs are poorly characterized. Our goal is to decipher this interplay between IFNγ-mediated host defense and chlamydial counterdefense, as such knowledge holds the potential to instruct the design of improved treatment options. To achieve this goal under Aim1, we designed unbiased functional genomics screens to identify human IFNγ-inducible genes (ISGs) that exert potent anti-Chlamydia defenses. In parallel we employ defined C. trachomatis mutant libraries in functional bacterial genetic screens to identify C. trachomatis genes that subvert ISG- driven defense pathways. As proof-of-principle we already identified i) human ISGs with not-previously- described anti-Chlamydia activities and ii) C. trachomatis mutants that are hyper-susceptible to IFNγ- activated host defenses in human cells. These novel human defense pathways and the corresponding C. trachomatis evasion mechanisms will be characterized through multidisciplinary approaches in Aim1. As an interrelated second aim, we will dissect the role of IFNγ in C. trachomatis-induced inflammation, which underlies Chlamydia-associated diseases. Although best known as a potent inducer of cell-intrinsic immunity, IFNγ also functions as a critical regulator of inflammation and associated diseases. We discovered that specific members of the superfamily of IFNγ-inducible dynamin-like GTPases control Chlamydia-induced activation of inflammasomes, a class of cytosolic immune sensors that drive inflammation. Using organoid and other mouse and human cell culture systems as well as novel in vivo mouse models, we will in Aim2 define the function of IFNγ-inducible GTPases in Chlamydia-triggered inflammation and in vivo pathogenesis. These studies will reveal critical insights into the role of IFNγ in the immunopathology of Chlamydia infections with the potential to guide the development of new therapeutic or prophylactic treatments or vaccine designs.

沙眼衣原体是最常见的细菌性性传播感染的原因。 美国。通常被称为无声流行病，沙眼衣原体在女性中的感染经常是 无症状，经常不被注意和治疗。感染可持续数月或数年， 最终导致盆腔炎、宫外孕和不孕。为了建立 持续感染，沙眼衣原体必须颠覆免疫的先天和适应性分支 系统。连接沙眼衣原体获得性免疫和先天免疫的中心节点是细胞因子。 干扰素(干扰素γ)。这种细胞因子是由T细胞等淋巴细胞产生的适应性免疫 系统，并在上皮细胞中诱导细胞固有的、天然的宿主对衣原体的防御。为了 克服干扰素γ介导的免疫并在人上皮细胞内复制，沙眼衣原体进化 专门针对其人类宿主进行的反击。这些沙眼衣原体的反防御和 相应的干扰素γ诱导的抗衣原体防御方案的特征很差。我们的 目的是破译干扰素γ介导的宿主防御和衣原体对抗防御之间的这种相互作用，因为 这些知识有可能指导改进治疗方案的设计。要做到这一点 目的在AIM1框架下，我们设计了无偏功能基因组学筛选，用于鉴定人干扰素γ诱导物 发挥强大的抗衣原体防御能力的基因(ISG)。同时，我们使用了定义的沙眼衣原体 功能细菌基因筛查突变文库鉴定沙眼衣原体ISG基因 驱使防御路径。作为原则的证明，我们已经确定了i)人类ISG不是-以前- 描述了抗衣原体活性和ii)沙眼衣原体突变株，它们对干扰素γ高度敏感- 激活了人体细胞的宿主防御系统。这些新的人类防御途径和相应的 沙眼衣原体逃避机制将通过多学科方法在Aim1中描述。AS 相关的第二个目标，我们将剖析干扰素γ在沙眼衣原体诱导的炎症中的作用， 是衣原体相关疾病的基础。尽管最为人所知的是细胞内源性的有效诱导剂 在免疫方面，干扰素γ也是炎症和相关疾病的关键调节因子。我们 发现干扰素γ诱导的动力素样GTP酶超家族的特定成员控制 衣原体诱导炎性小体的激活，炎性小体是一类胞质免疫传感器，负责驱动 发炎。利用有机物和其他小鼠和人的细胞培养系统以及体内的新技术 小鼠模型，我们将在AIM2中定义干扰素γ诱导的GTP酶在衣原体触发的功能中的作用 炎症和体内发病机制。这些研究将揭示干扰素γ在人类免疫缺陷中的重要作用。 衣原体感染的免疫病理学可能指导新的治疗或治疗方法的开发 预防性治疗或疫苗设计。