Modulation of Host Cell Responses by Francisella tularensis

土拉弗朗西斯菌对宿主细胞反应的调节

基本信息

批准号：
10159857
负责人：
David G Thanassi
金额：
$ 54.95万
依托单位：
STATE UNIVERSITY NEW YORK STONY BROOK
依托单位国家：
美国
项目类别：
财政年份：
2019
资助国家：
美国
起止时间：
2019-06-10 至 2024-05-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/10159857
关键词：
Address Amino Acids Apoptosis Apoptotic Bacteria Bioterrorism CASP3 gene Cell Death Cells Centers for Disease Control and Prevention (U.S.)Cytosol Data Detection Development Disease Dose Environment Equilibrium Foundations Francisella Francisella tularensis Genes Goals Host Defense Host Defense Mechanism Human Immune Immune response Infection Inhalation Innate Immune Response Ion Channel Knowledge Lead Life Style Link Mediating Modeling Molecular Morbidity - disease rate Oxidative Stress Pathogenesis Pathogenicity Pathway interactions Pneumonia Prevention Protein Secretion Proteins Publishing Role Route Signal Pathway System Testing Therapeutic Agents Time Tissues Toxin Tularemia Universities Vaccines Virulence Virulence Factors Virulent Work Zoonoses aerosolized cytokine defined contribution genetic approach immunoregulation improved in vivo insight macrophage medical countermeasure mortality novel therapeutic intervention novel therapeutics pathogen pathogenic bacteria preservation response

项目摘要

PROJECT SUMMARY Francisella tularensis is the causative agent of the zoonotic disease tularemia. F. tularensis is a highly virulent intracellular pathogen that is easily transmitted to humans when aerosolized and thus has the potential for use as a bioterrorism agent. The molecular basis for the high infectivity and virulence of F. tularensis is not well understood. As an intracellular pathogen, F. tularensis must evade cellular innate immune detection; however, a mechanistic understanding for how F. tularensis subverts the host response during infection is lacking. We have identified TolC as critical for the virulence of F. tularensis. TolC is an outer membrane channel protein involved in both multidrug efflux and the secretion of a wide range of bacterial effector proteins by the type I protein secretion pathway. We have evidence that factors secreted via TolC function to dampen innate immune responses of the host, including programmed cell death pathways, providing the bacteria extended time to replicate within the protected intracellular niche and prolonging survival within host tissues, thereby tipping the host-pathogen balance in favor of the pathogen. These host suppressive activities related to TolC function are likely key to the successful intracellular lifestyle of F. tularensis and critical to its extreme virulence. This proposal will investigate the mechanism of TolC in Francisella pathogenesis, with the overall goal of revealing molecular details by which intracellular pathogens interact with host cells, evade host defenses, and manipulate host responses. The first aim of the proposal will define the role of TolC in modulation of host responses during in vivo infection and the connection of these activities to F. tularensis virulence. The second aim of the proposal will identify Francisella effectors secreted via TolC, and by other routes, during host cell infection and will determine genes required for TolC-dependent subversion of host cell death pathways. The third aim of the proposal will determine the mechanism by which F. tularensis suppresses macrophage innate immune responses during infection in a TolC-dependent manner. Data generated by this proposal will lead to a detailed, mechanistic understanding of TolC function in F. tularensis. The identification of effectors or toxins secreted by F. tularensis would represent a significant advance for the field. This proposal will not only lead to better knowledge of F. tularensis virulence mechanisms, but will also provide new insights into strategies used by intracellular pathogens to survive within the host and cause disease.

项目概要土拉弗朗西斯菌是人畜共患土拉热病的病原体。 F. tularensis 是一种高毒力的细胞内病原体，雾化时很容易传播给人类，因此具有利用潜力作为生物恐怖主义代理人。土拉弗朗西斯菌高传染性和毒力的分子基础尚不明确明白了。作为一种细胞内病原体，土拉弗朗西斯菌必须逃避细胞先天免疫检测；然而，目前还缺乏对土拉弗拉菌在感染过程中如何破坏宿主反应的机制了解。我们已确定 TolC 对土拉弗朗西斯菌的毒力至关重要。 TolC 是一种外膜通道蛋白参与多药流出和 I 型细菌效应蛋白的分泌蛋白质分泌途径。我们有证据表明，通过 TolC 分泌的因子可抑制先天免疫宿主的反应，包括程序性细胞死亡途径，为细菌提供了更长的时间在受保护的细胞内生态位内复制并延长宿主组织内的存活时间，从而使宿主-病原体平衡有利于病原体。这些与 TolC 功能相关的宿主抑制活动是这可能是土拉弗拉菌成功的细胞内生活方式的关键，也是其极端毒力的关键。这个提议将研究 TolC 在弗朗西斯菌发病机制中的机制，总体目标是揭示分子机制细胞内病原体与宿主细胞相互作用、逃避宿主防御和操纵宿主的详细信息回应。该提案的第一个目标是定义 TolC 在宿主反应调节中的作用。体内感染以及这些活动与 F. tularensis 毒力的联系。该提案的第二个目标将识别宿主细胞感染期间通过 TolC 和其他途径分泌的弗朗西斯菌效应子，并且将确定 TolC 依赖性破坏宿主细胞死亡途径所需的基因。第三个目标该提案将确定 F. tularensis 抑制巨噬细胞先天免疫的机制感染期间以 TolC 依赖性方式做出反应。该提案生成的数据将导致详细的、对 F. tularensis 中 TolC 功能的机制理解。识别效应物或分泌的毒素 F. tularensis 将代表该领域的重大进步。这项建议不仅会带来更好的结果土拉热镰刀菌毒力机制的知识，但也将为土拉热镰刀菌所使用的策略提供新的见解细胞内病原体在宿主体内存活并引起疾病。