Virulence Mechanism of Y. pestis and tularensis

鼠疫耶尔森菌和土拉尔菌的毒力机制

• 批准号: 6730804
• 负责人: David G Thanassi
• 金额: $ 36.39万
• 依托单位: STATE UNIVERSITY NEW YORK STONY BROOK
• 依托单位国家: 美国
• 财政年份: 2003
• 资助国家: 美国
• 起止时间: 2003-09-01 至 2008-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/6730804
• 关键词: Francisella tularensis; SDS polyacrylamide gel electrophoresis; Yersinia pestis; Yersinia pestis disease; bacteria infection mechanism; bioinformatics; bioterrorism /chemical warfare; electron microscopy; gene expression; gene expression profiling; laboratory mouse; mass spectrometry; microarray technology; molecular chaperones; polymerase chain reaction; tularemia; virulence

Yersinia pestis and Francisella tularensis are the causative agents of plague and tularemia, respectively. Both of these bacteria are extremely virulent for humans when aerosolized and thus have the potential for use as agents of bioterrorism. Greater knowledge of the molecular mechanisms underlying Y. pestis and F. tularensis pathogenesis is urgently needed. The goals of this proposal are to characterize Y. pestis and F. tularensis virulence factors and to elucidate mechanisms of virulence factor biogenesis. Genome sequencing of Y. pestis revealed the presence of ten chaperone/usher secretion pathways, eight of which were previously unknown. Chaperone/usher pathways are utilized by a broad range of bacterial pathogens for the biogenesis of virulence-associated surface structures. The first specific aim of this proposal is to investigate the chaperone/usher pathways of Y. pestis. Expression of the novel pathways will be determined and the roles of the pathways in pathogenesis will be tested by aerosol infection of mice. Pathways with a virulence phenotype will be selected for further analysis. In addition, detailed analysis of F1 capsule biogenesis by the previously known caf chaperone/usher pathway will be performed. The F1 capsule is the major protective antigen of K pestis. The molecular basis for the virulence of F. tularensis is largely unknown. The second specific aim of this proposal is to identify and characterize potential virulence factors of F. tularensis, focusing on surface and secreted proteins. A bioinformatics approach will be used to mine the F. tularensis genome for secretion systems, secreted proteins and surface structures. Ultrastructural and biochemical methods will be used to directly visualize and isolate F. tularensis surface structures and secreted proteins. Potential virulence factors will be tested for their roles in pathogenesis by aerosol infection of mice. This proposal will be done in close collaboration with the other Projects and Core facilities of the Program Project Grant entitled "Agents of Bioterrorism: Pathogenesis and Host Defense." The work described in this proposal and the Program Project Grant will provide insights into the pathogenesis of Y. pestis and F. tularensis, and create opportunities for the development of novel methods to detect, prevent and treat outbreaks of plague or tularemia.

鼠疫耶尔森氏菌和土拉热弗朗西丝氏菌分别是鼠疫和土拉菌病的病原体。这两种细菌在雾化时对人类都是极其致命的，因此有可能用作生物恐怖主义的代理人。对Y. pestis和F.土拉热病的发病机制是迫切需要的。这个提议的目标是描述Y。pestis和F.目的研究土拉菌毒力因子的生物合成机制。Y.鼠疫揭示了10个伴侣/usher分泌途径的存在，其中8个以前是 未知伴侣/引导途径被广泛的细菌病原体用于与毒性相关的表面结构的生物发生。该建议的第一个具体目标是研究Y.鼠疫将确定新途径的表达，并通过小鼠的气溶胶感染来测试途径在发病机制中的作用。将选择具有毒力表型的途径进行进一步分析。此外，将通过先前已知的caf伴侣/usher途径对F1荚膜生物发生进行详细分析。F1胶囊是主要的保护 鼠疫杆菌抗原对F.土拉热病在很大程度上是未知的。该建议的第二个具体目标是鉴定和表征F. tularensis，专注于表面和分泌蛋白。生物信息学的方法将被用来挖掘F。tularensis基因组的分泌系统，分泌蛋白和表面结构。将采用超微结构和生物化学方法直接观察和分离F。土拉菌表面结构和分泌蛋白。将通过小鼠气溶胶感染测试潜在毒力因子在发病机制中的作用。这项建议将与题为“生物恐怖主义的代理人：发病机制和宿主防御”的计划项目赠款的其他项目和核心设施密切合作。“这篇文章中描述的工作 该提案和计划项目赠款将提供深入了解Y的发病机制。pestis和F.土拉菌病，并为开发检测、预防和治疗鼠疫或土拉菌病爆发的新方法创造机会。