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

• 批准号: 10404108
• 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
• 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/10404108
• 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

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.

项目总结 图拉氏方济氏菌是人畜共患病图拉热症的病原体。图拉氏丝孢杆菌是一种高度致病的 气雾化时很容易传播给人类的细胞内病原体，因此有可能使用 作为一名生物恐怖主义特工。图拉氏狸殖吸虫高感染性和致病力的分子基础尚不清楚 明白了。作为一种细胞内病原体，图拉氏原虫必须躲避细胞的天然免疫检测；然而， 关于图拉氏丝虫在感染过程中如何颠覆宿主反应的机械性理解尚不清楚。我们 已经确定TolC对图拉氏丝虫的毒力至关重要。TolC是一种外膜通道蛋白 参与多种药物的外排和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功能分泌的因子可以抑制先天免疫 宿主的反应，包括程序化的细胞死亡途径，为细菌提供延长的时间 在受保护的细胞内利基内复制并延长宿主组织内的存活时间，从而使 寄主-病原菌的平衡有利于病原菌。这些与TolC功能相关的宿主抑制活动包括 可能是图拉氏丝虫成功的细胞内生活方式的关键，也是其极端毒力的关键。这项建议 将研究TolC在弗氏杆菌致病机制中的作用，总的目标是揭示分子 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细节 回应。该提案的第一个目标将定义TolC在调节宿主反应方面的作用 活体感染及其活性与图拉氏肺吸虫毒力的关系。该提案的第二个目的是 将在宿主细胞感染期间识别通过TolC和其他途径分泌的弗朗西塞氏菌效应物 确定依赖TolC颠覆宿主细胞死亡途径所需的基因。的第三个目标 该提案将确定图拉氏杆菌抑制巨噬细胞天然免疫的机制 感染过程中的反应依赖于TolC。这项提案产生的数据将导致详细的、 图拉氏沼虾TolC功能的机制认识。识别效应物质或毒素的分泌 图拉氏赤霉菌将代表着该领域的重大进步。这项提议不仅会带来更好的 对图拉氏丝孢杆菌毒力机制的了解，但也将为 细胞内的病原体在宿主体内生存并引起疾病。