Mechanism of TolC in the virulence of Francisella tularensis

TolC对土拉弗朗西斯菌的毒力机制

基本信息

批准号：
9089865
负责人：
David G Thanassi
金额：
$ 19.51万
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：
2015
资助国家：
美国
起止时间：
2015-06-15 至 2018-05-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/9089865
关键词：
Address Antigens Area Attenuated Attenuated Vaccines Bacteria Bioterrorism Breathing Cell Culture Techniques Cell Death Centers for Disease Control and Prevention (U.S.)Classification Data Defect Development Disease E coli tolC protein Equilibrium Foundations Francisella Francisella tularensis Goals Health Host Defense Human Immune response Infection Ion Channel Knowledge Lead Life Style Medical Modeling Molecular Mus Mutation Pathogenesis Pathway interactions Phenotype Physiological Prevention Prevention approach Process Protein Secretion Proteins Proteomics Publishing Research Role Solid Testing Therapeutic Therapeutic Agents Time Tissues Toxin Tularemia Vaccines Virulence Virulence Factors Virulent Work aerosolized base defined contribution disorder prevention genetic approach improved insight macrophage mouse model mutant novel novel therapeutics pathogen response

项目摘要

DESCRIPTION (provided by applicant): Francisella tularensis is the causative agent of the zoonotic disease tularemia. F. tularensis is a highly virulent intracellular pathogen that is easil 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. We have identified TolC as critical for the virulence of F. tularensis. TolC is an oute membrane channel protein involved in both multidrug efflux and the secretion of virulence factors by the type I protein secretion pathway. We have evidence that effector proteins secreted via TolC function to dampen host cell death responses during infection. This provides the bacteria extended time to replicate within the protected intracellular niche and prolongs 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 and extreme virulence of F. tularensis. This proposal will generate critica new information about the mechanism of TolC in Francisella pathogenesis. The first aim of the proposal will define the contributions of TolC to the virulence of the human pathogenic F. tularensis Schu S4 strain. The second aim of the proposal will use complementary approaches to identify the virulence factors secreted via TolC. This proposal will not only lead to better knowledge of F. tularensis virulence mechanisms, but will also provide insights into mechanisms by which intracellular pathogens survive in the host and cause disease.

描述（由适用提供）：弗朗西斯氏菌是人畜共患病的病因。 F. toarlensis是一种高毒的细胞内病原体，在雾化时很容易传播给人类，因此有可能用作生物恐怖剂。尚未充分了解f氏菌的高感染和病毒的分子基础。我们已经确定TOLC对于F. tularensis的病毒至关重要。 TOLC是一种参与多药外排和通过I型蛋白质分泌途径的病毒因子分泌的出口膜通道蛋白。我们有证据表明，通过TOLC功能分泌的效应蛋白在感染过程中为Damen宿主细胞死亡反应分泌。这为细菌提供了延长的时间，以在受保护的细胞内生态裂市场内复制并延长宿主组织内的生存，从而将宿主 - 病原体平衡倾斜以支持病原体。这些与TOLC功能相关的宿主抑制活动可能是F. toarlensis的成功细胞内生活方式和极端病毒的关键。该提案将产生有关Francisella发病机理中TOLC机制的关键新信息。该提案的第一个目的将定义TOLC对人类致病性链霉菌Schu S4菌株病毒的贡献。该提案的第二个目的将采用完整的方法来识别通过TOLC分泌的病毒因素。该提案不仅会更好地了解F. tuarlenensis病毒机制，而且还将提供有关细胞内病原体在宿主中生存并引起疾病的机制的见解。