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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

基本信息

批准号：
10329900
负责人：
Joern Coers
金额：
$ 45.78万
依托单位：
DUKE UNIVERSITY
依托单位国家：
美国
项目类别：
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/10329900
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 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 T-Lymphocyte Therapeutic Therapeutic Intervention United States Vaccine Design Vaccines Vacuole Virulence Factors Woman Work adaptive immunity bacterial genetics chronic infection cytokine design endometrial organoid 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 vaccine strategy

项目摘要

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的女性沙眼衣原体感染经常发生无症状，并且经常被忽视和治疗。感染可能持续数月或数年，最终导致盆腔炎、宫外孕、不孕不育。为了建立为了持续感染，沙眼衣原体必须破坏免疫系统的先天性和适应性分支系统。将适应性免疫和先天免疫与沙眼衣原体连接起来的中心节点是细胞因子 γ-干扰素（IFNγ）。这种细胞因子由淋巴细胞产生，例如适应性免疫的 T 细胞系统并诱导上皮细胞中细胞内在的、先天的宿主针对衣原体的防御。为了沙眼衣原体克服了 IFNγ 介导的免疫并在人上皮细胞内复制专门适应人类宿主的反防御措施。这些沙眼衣原体的防御措施和 IFNγ诱导的抗衣原体防御程序的相应功能尚不清楚。我们的目标是破译 IFNγ 介导的宿主防御和衣原体反防御之间的相互作用，如这些知识有可能指导改进治疗方案的设计。为了实现这一目标为了实现 Aim1 的目标，我们设计了无偏见的功能基因组学筛选来识别人类 IFNγ 诱导型发挥有效抗衣原体防御作用的基因（ISG）。同时我们使用定义的沙眼衣原体功能性细菌遗传筛选中的突变体文库，以鉴定破坏 ISG- 的沙眼衣原体基因驱动的防御途径。作为原理证明，我们已经确定了 i) 人类 ISG 具有以前没有的- 描述了抗衣原体活性和 ii) 对 IFNγ 高度敏感的沙眼衣原体突变体 - 激活人体细胞中的宿主防御。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 Aim1 中的多学科方法进行表征。作为相互关联的第二个目标是，我们将剖析 IFNγ 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。尽管最著名的是作为细胞内在的有效诱导剂除了免疫之外，IFNγ 还作为炎症和相关疾病的关键调节因子。我们发现 IFNγ 诱导型动态 GTP 酶超家族的特定成员控制衣原体诱导的炎症小体激活，炎症小体是一类细胞质免疫传感器，可驱动炎。使用类器官和其他小鼠和人类细胞培养系统以及新颖的体内细胞培养系统小鼠模型，我们将在 Aim2 中定义 IFNγ 诱导型 GTPases 在衣原体触发中的功能炎症和体内发病机制。这些研究将揭示 IFNγ 在衣原体感染的免疫病理学有可能指导新疗法或新疗法的开发预防性治疗或疫苗设计。