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：
8969771
负责人：
David G Thanassi
金额：
$ 23.46万
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 2017-05-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/8969771
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 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 public health relevance 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.

Description: Francisella Tularensis is the Causative agent of the Zoonotic Disease Tuleremia. Rulent Intracellular Pathogen THASIL TRANSMITTED TO HUMANS WHEN AEROSOLIZED AND THE POTENTIAL FOR FOR ASE ASE ASE ASE BITERRORISM AGEL. ECULAR BASIS FOR THE INFECTIVY AND VIRULENCE OF F. TULARENSIS Is WELL UNDERSTOOD. larensis。在宿主的宿主平衡中延长了宿主的生存，以延长与病原体相关的宿主的生存。 Francisella athogeness中的TOLC的新信息。对F. toarlensis机制的了解得太高，但也将提供给宿主中细胞内病原体并引起疾病的机制。