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Functional genomics for Chlamydia

衣原体功能基因组学

基本信息

批准号：
9355419
负责人：
P Scott Hefty
金额：
$ 2.26万
依托单位：
UNIVERSITY OF WASHINGTON
依托单位国家：
美国
项目类别：
财政年份：
2017
资助国家：
美国
起止时间：
2017-03-01 至 2021-04-30
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/9355419
关键词：
Achievement Acute Address Bacteria Biological Biology Cells Chlamydia Chlamydia Infections Chlamydia trachomatis Clinical Complex Cultured Cells DNA DNA Sequence Alteration Data Defect Development Disease Environment Epithelial Cells Essential Genes Female Foundations Frequencies Genes Genetic Genetic Recombination Genetic study Genome Genomics Goals Growth Growth and Development function Horizontal Gene Transfer Human Immune response In Vitro Individual Infection Influentials Integration Host Factors Investigation Knowledge Libraries Mediating Metabolic Pathway Modeling Modernization Molecular Mus Mutagenesis Mutation Natural History Nature Organism Parasites Pathogenesis Pathology Phenotype Play Reproductive Health Resources Role Sequence Analysis Sexually Transmitted Diseases Shapes System Technology Transfer Temperature Time Tropism Virulence Work base clinically relevant conditional mutant functional genomics gene product genetic manipulation genome-wide in vivo loss of function microorganism mouse model mutant novel novel strategies pathogen pressure protein function reproductive tract temperature sensitive mutant tool

项目摘要

PROJECT SUMMARY/ABSTRACT For bacterial pathogens, the first studies that begin to define the microorganism’s functional genetic nature on a genome-wide scale, frequently represent a landmark and highly impactful achievement. The major human pathogen, Chlamydia trachomatis, is a bacterium for which such studies have not been performed, in large part due to Chlamydia’s obligate intracellular nature and historical intractability to modern genetic perturbations. With the development of two major genetic tools for Chlamydia by our group—transposon mutagenesis and conditional temperature-sensitive mutants—functional genomic investigations in Chlamydia are now possible. Our long term goal is to globally define and functionally characterize the genetic correlates to C. trachomatis infection and pathogenesis. Using the new approaches described above, we propose to: (i) build defined mutant libraries of transposon and temperature-sensitive conditional mutants in model Chlamydia strains, (ii) screen these libraries for hallmark in vitro and in vivo growth defects using a clinically relevant murine genital tract model, and (iii) determine the Chlamydia genes associated with host adaptation by exploiting interspecies lateral gene transfer for Chlamydia and the inability of human parental strains to infect mice. These efforts are essential for gaining a functional appreciation of the role chlamydial genes play in the organism’s growth and development, and also Chlamydia’s evolutionary adaptation to successfully maintain infection and pathogenesis in complex mammalian hosts. We anticipate that Chlamydia will serve as a model obligate intracellular bacterium, and, therefore, the knowledge obtained from this work will broadly extend to other pathogens that have similarly evolved an obligate intracellular niche in their mammalian hosts. Identification of these loci is critical for our understanding the mechanism of Chlamydia adaptation to mammalian hosts, and is an important step towards elucidating the major virulence correlates of C. trachomatis in humans.

项目概要/摘要对于细菌病原体，第一个研究开始定义微生物的功能遗传性质在全基因组范围内，通常代表着具有里程碑意义和极具影响力的成就。主要人类病原体沙眼衣原体是一种细菌，在很大程度上尚未对其进行此类研究由于衣原体的专性细胞内性质和历史上对现代遗传扰动的难处理性。我们课题组开发了两种主要的衣原体遗传工具——转座子诱变和条件温度敏感突变体——衣原体功能基因组研究现在成为可能。我们的长期目标是在全球范围内定义和功能表征遗传相关性沙眼衣原体感染和发病机制。使用上述新方法，我们建议： (i) 在模型中建立转座子和温度敏感条件突变体的明确突变体库衣原体菌株，(ii) 使用临床试验筛选这些文库的体外和体内生长缺陷标志相关的小鼠生殖道模型，以及（iii）确定与宿主适应相关的衣原体基因通过利用衣原体的种间横向基因转移以及人类亲本菌株的无能力感染老鼠。这些努力对于获得衣原体基因在生物体的生长和发育，以及衣原体成功维持的进化适应复杂哺乳动物宿主的感染和发病机制。我们预计衣原体将作为模型专性细胞内细菌，因此，从这项工作中获得的知识将广泛扩展到其他病原体在其哺乳动物宿主中也类似地进化出专性细胞内生态位。这些位点的鉴定对于我们理解衣原体适应机制至关重要哺乳动物宿主，这是阐明主要毒力相关因素的重要一步人类沙眼衣原体。