Francisella tularensis Pathogenesis

土拉弗朗西斯菌发病机制

• 批准号: 8298619
• 负责人: Thomas H KAWULA
• 金额: $ 36.22万
• 依托单位: UNIV OF NORTH CAROLINA CHAPEL HILL
• 依托单位国家: 美国
• 财政年份: 2010
• 资助国家: 美国
• 起止时间: 2010-08-16 至 2014-07-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8298619
• 关键词: Affect; Animals; Bacteria; Binding Proteins; Biochemical; Bioinformatics; Biological; Biology; Cell membrane; Cells; Characteristics; Containment; Cytoplasm; Dendrites; Development; Environment; Epithelial Cells; Escape Mutant; Francisella; Francisella tularensis; Frequencies; Genes; Genetic; Goals; Gram-Negative Bacterial Infections; Growth; Human; Immune response; Immunoprecipitation; Immunosuppression; Infection; Inflammatory; Invaded; Laboratories; Lung diseases; Maps; Membrane Proteins; Methods; Modeling; Mutagenesis; Mutation; Open Reading Frames; Organism; Orthologous Gene; Pathogenesis; Phagosomes; Phenotype; Post-Translational Protein Processing; Property; Proteins; Regulation; Research; Role; Sequence Homology; Site; Site-Directed Mutagenesis; Structure; Testing; Time; Transmembrane Domain; Virulence; Virulent; Yeasts; cell type; cytokine; genetic analysis; insight; macrophage; mutant; pathogen; periplasm; public health relevance; resilience; tool; yeast two hybrid system

DESCRIPTION (provided by applicant): Francisella tularensis is an extremely virulent Gram negative, facultative intracellular bacterial pathogen capable of causing rapidly progressing lethal infections in literally hundreds of diverse animal species, including humans. Although the general properties of Francisella virulence and pathogenesis are understood, the function of any one Francisella protein not assured by sequence homology remains essentially unknown. This situation is due, in part, to the fact that most open reading frames in Francisella have no known orthologs. Our goal is to uncover and experimentally determine unknown mechanisms and properties that contribute to virulence and pathogenesis. Herein we propose to define the function of RipA, which is a cytoplasmic membrane protein that is conserved among Francisella and is required for adaptation to the host cell environment. This goal will be accomplished through genetic and phenotypic analysis of ripA mutants and extragenic suppressors of ripA mutant phenotypes, identification of RipA - binding proteins, biophysical studies on RipA topology and structure, and regulation of ripA expression. PUBLIC HEALTH RELEVANCE: We are focused on understanding the bacterial properties of Francisella tularensis that make this organism such a highly virulent pathogen for humans, particularly with respect to pulmonary disease. In this application we will study the biological properties of a limited number of cellular components that are unique to Francisella and determine their contribution to Francisella virulence and pathogenesis.

描述（由申请人提供）：土拉热弗朗西丝菌是一种极致命的革兰氏阴性兼性细胞内细菌病原体，能够在包括人类在内的数百种不同动物物种中引起快速进展的致死性感染。虽然弗朗西斯菌的毒力和发病机制的一般性质是了解的，任何一个弗朗西斯菌蛋白质的功能不保证序列同源性仍然基本上是未知的。这种情况部分是由于Francisella中的大多数开放阅读框架没有已知的直系同源物。我们的目标是发现和实验确定未知的机制和属性，有助于毒力和发病机制。在这里，我们建议定义RipA的功能，这是一种胞质膜蛋白，在弗朗西斯菌中是保守的，是适应宿主细胞环境所必需的。这一目标将通过对ripA突变体和ripA突变体表型的基因外抑制子的遗传和表型分析、对RipA结合蛋白的鉴定、对RipA拓扑结构和结构的生物物理研究以及对ripA表达的调控来实现。 公共卫生关系：我们专注于了解土拉热弗朗西斯菌的细菌特性，使这种生物体成为人类的高致病性病原体，特别是在肺部疾病方面。在本申请中，我们将研究弗朗西斯菌所特有的有限数量的细胞组分的生物学特性，并确定它们对弗朗西斯菌毒力和致病性的贡献。