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.

项目摘要 Francisella tularensis是人畜共患病的病因。 F. tularensis是一种高度毒 雾化后容易传播给人类的细胞内病原体，因此具有使用的潜力 作为生物恐怖剂。 F. tularensis的高感染率和毒力的分子基础不好 理解。作为细胞内病原体，F。tuarlensis必须逃避细胞先天免疫检测。然而， 对tularensis如何颠覆感染期间宿主反应的机械理解。我们 已经确定TOLC对于F. tularensis的毒力至关重要。 TOLC是一种外膜通道蛋白 通过I型I类细菌效应蛋白的多种果外排出和分泌多种细菌效应蛋白 蛋白质分泌途径。我们有证据表明，通过TOLC功能分泌的因素可以抑制先天免疫 宿主的反应，包括编程的细胞死亡途径，提供了细菌延长的时间 在受保护的细胞内生态位和延长宿主组织内的生存中复制，从而倾斜 宿主 - 病原体平衡有利于病原体。这些与TOLC功能有关的宿主抑制活动是 成功的细胞内生活方式的关键可能是f霉菌的极端毒力至关重要。这个建议 将研究Francisella发病机理中TOLC的机制，其总体目标是揭示分子 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 回答。该提案的第一个目的将定义TOLC在调节宿主反应中的作用 体内感染以及这些活性与F. tularensis毒力的联系。提案的第二个目标 将在宿主细胞感染过程中识别通过TOLC和其他路线分泌的Francisella效应子，并将 确定宿主细胞死亡途径的TOLC依赖性颠覆所需的基因。第三个目标 提案将确定F. tularensis抑制巨噬细胞先天免疫的机制 以TOLC依赖性方式感染期间的反应。该提案生成的数据将导致详细的， F. tularensis中TOLC功能的机械理解。鉴定效应子或毒素由 F. tularensis将代表该领域的重大进步。该提议不仅会带来更好的 对f。tularensis毒力机制的了解，但还将提供对使用的策略的新见解 细胞内病原体生存在宿主中并引起疾病。