Defining human interferon-stimulated genes with novel functions in host defense to Chlamydia infections

定义在宿主防御衣原体感染方面具有新功能的人干扰素刺激基因

基本信息

  • 批准号:
    9911637
  • 负责人:
  • 金额:
    $ 3.75万
  • 依托单位:
  • 依托单位国家:
    美国
  • 项目类别:
  • 财政年份:
    2020
  • 资助国家:
    美国
  • 起止时间:
    2020-03-01 至 2023-02-28
  • 项目状态:
    已结题

项目摘要

ABSTRACT Chlamydia trachomatis is the most widespread sexually transmitted bacterial pathogen in the world. People infected with C. trachomatis are often initially asymptomatic, hindering the proper diagnostic and therapeutic strategies necessary to impede this “silent epidemic”. If not properly treated, the bacteria are able to establish a long-lasting, persistent infection that can ultimately lead to severe medical sequelae. These complications arise predominantly in women, and include pelvic inflammatory disease, life-threatening ectopic pregnancies or infertility. A critical component of the microbial pathogenesis of C. trachomatis is its ability to evade immune detection and other antimicrobial responses conferred by its human host. These host defenses are largely galvanized by the cytokine interferon-gamma (IFNγ), which stimulates epithelial cells occupying the site of an infection to up regulate the expression of interferon-stimulated-genes (ISGs). These ISGs are then responsible for the execution and immune clearance of invading microbes. In order to subvert the effects of IFNγ and successfully replicate in epithelial cells, C. trachomatis must have evolved counterdefenses to ISGs that normally target and destroy other bacterial pathogens. However, the identity and function of these ISGs, as well as the C. trachomatis virulence effectors that inhibit ISG functions, are poorly understood. In pursuit of answering these questions, we performed two complementary screens to identify i) ISGs with anti-Chlamydia activities and ii) C. trachomatis genetic mutants with hypersensitivity to IFNγ treatment. In Aim 1 of this proposal, we will use a combination of functional genetics and cell biological studies in human cells to dissect the intracellular responses conferred by these anti-Chlamydia ISGs. In Aim 2, we will combine parallel approaches in bacterial genetics and whole-genome sequencing to pinpoint the causative genetic elements responsible for C. trachomatis evasion of IFNγ-mediated immunity. Taken together, these experiments will interrogate the dynamic relationship between cell-intrinsic defenses mediated by human ISGs and counter- resistance mechanisms of Chlamydia that are employed during infection. Implications of these studies will provide important platforms for the development of novel anti-Chlamydia medicines or vaccination strategies that treat its associated disease.
摘要 沙眼衣原体是世界上最广泛的性传播细菌病原体。 感染C.沙眼最初通常无症状,妨碍了正确的诊断, 治疗策略,以阻止这种“沉默的流行病”。如果不适当处理,细菌能够 建立一个长期的,持续的感染,最终可能导致严重的医疗后遗症。这些 并发症主要发生在女性,包括盆腔炎,危及生命的异位妊娠, 怀孕或不育。是C.沙眼是它的能力, 逃避免疫检测和其他由其人类宿主赋予的抗菌反应。这些宿主防御系统 在很大程度上是由细胞因子干扰素γ(IFNγ)刺激的,IFN γ刺激上皮细胞占据 感染部位,以上调干扰素刺激基因(ISG)的表达。这些ISG是 负责执行和免疫清除入侵的微生物。为了颠覆 IFNγ在上皮细胞中成功复制,C.沙眼病毒一定进化出了对ISG的反防御 它们通常以其他细菌病原体为目标并消灭它们。然而,这些ISG的身份和职能, 以及C.沙眼衣原体毒力效应子抑制ISG功能的机制尚不清楚。为了追求 为了回答这些问题,我们进行了两次互补筛选,以鉴定i)具有抗衣原体的ISG (二)C。对IFNγ治疗超敏的沙眼衣原体基因突变体。目标1 建议,我们将使用功能遗传学和细胞生物学研究相结合,在人类细胞解剖 由这些抗衣原体ISG赋予的细胞内反应。在目标2中,我们将联合收割机 细菌遗传学和全基因组测序方法,以查明致病遗传因素 负责C。沙眼衣原体逃避IFNγ介导的免疫。综合起来,这些实验将 询问由人ISGs介导的细胞内在防御与反 衣原体在感染过程中的抵抗机制。这些研究的意义将 为开发新型抗衣原体药物或疫苗接种策略提供重要平台 来治疗相关疾病

项目成果

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Stephen Charles Walsh其他文献

Stephen Charles Walsh的其他文献

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{{ truncateString('Stephen Charles Walsh', 18)}}的其他基金

Defining human interferon-stimulated genes with novel functions in host defense to Chlamydia infections
定义在宿主防御衣原体感染中具有新功能的人干扰素刺激基因
  • 批准号:
    10359068
  • 财政年份:
    2020
  • 资助金额:
    $ 3.75万
  • 项目类别:

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