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：
Stephen Charles Walsh
金额：
$ 3.75万
依托单位：
DUKE UNIVERSITY
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

来源：
https://reporter.nih.gov/project-details/9911637
关键词：
Acids Anti-Bacterial Agents Antibacterial Response Bacteria Biological Biological Assay Biology Cells Chlamydia Chlamydia Infections Chlamydia muridarum Chlamydia trachomatis Coenzyme A Detection Development Diagnostic Disease Ectopic Pregnancy Environment Enzymes Epidemic Epithelial Cells Genes Genetic Genetic Screening Genomics Growth Host Defense Human Hypersensitivity Immune Immune response Immune system Immunity Infection Infertility Interferon Type II Interferons Interleukins Invaded Lead Life Ligase Lipids Mediating Medical Medicine Microbe Microscopic Molecular Mus Natural Immunity Nature Pathogenesis Pathogenicity Pelvic Inflammatory Disease Pharmaceutical Preparations Phenotype Proteins Resistance Role Sexual Transmission Single Nucleotide Polymorphism Site Techniques Testing Therapeutic Vaccines Virulence Virulence Factors Woman Work antimicrobial bacterial genetics base causal variant chronic infection cytokine experimental study functional genomics gene function genetic element genetic variant genome sequencing immune clearance improved long chain fatty acid medical complication microbial mutant mycobacterial novel pathogen pathogenic bacteria pathogenic microbe programs prophylactic resistance mechanism response small molecule libraries trait vaccination strategy whole genome

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.

抽象的沙眼衣原体是世界上最广泛的性传播细菌病原体。感染沙眼衣原体的人最初通常没有症状，这妨碍了正确的诊断和治疗阻止这种“沉默的流行病”所需的治疗策略如果治疗不当，细菌就能够传播。建立长期、持续的感染，最终可能导致严重的医疗后遗症。并发症主要出现在女性身上，包括盆腔炎、危及生命的异位沙眼衣原体微生物发病机制的一个关键组成部分是其感染的能力。逃避人类宿主赋予的免疫检测和其他抗菌反应。很大程度上受到细胞因子干扰素γ (IFNγ) 的刺激，它刺激占据上皮细胞的上皮细胞然后，在感染部位上调干扰素刺激基因 (ISG) 的表达。负责执行和免疫清除入侵微生物，以颠覆其影响。 IFNγ 并在上皮细胞中成功复制，沙眼衣原体一定已经进化出了针对 ISG 的反防御能力通常以其他细菌病原体为目标并消灭它们，但是这些 ISG 的特性和功能，以及抑制 ISG 功能的沙眼衣原体毒力效应子，人们对它知之甚少。为了回答这些问题，我们进行了两次补充筛选来识别 i) 具有抗衣原体的 ISG 活性和 ii) 对 IFNγ 治疗过敏的沙眼衣原体基因突变体。建议，我们将结合功能遗传学和细胞生物学研究对人类细胞进行剖析在目标 2 中，我们将结合平行的这些抗衣原体 ISG 所赋予的细胞内反应。细菌遗传学和全基因组测序方法可查明致病遗传元件沙眼衣原体逃避 IFNγ 介导的免疫综上所述，这些实验将探究人类 ISG 介导的细胞内在防御和反作用之间的动态关系这些研究的意义将是衣原体在感染过程中的耐药机制。为开发新型抗衣原体药物或疫苗接种策略提供重要平台治疗其相关疾病。