Francisella tularensis Pathogenesis

描述(申请人提供)：图拉方济氏菌是一种极具毒性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中引起迅速发展的致命感染。虽然人们已经了解了链球菌毒力和致病机制的一般特性，但任何一种未被序列同源性确定的链球菌蛋白的功能基本上仍然未知。这种情况的部分原因是，弗朗西塞拉的大多数开放阅读框架没有已知的同源基因。我们的目标是发现并在实验上确定导致毒力和发病机制的未知机制和特性。在这里，我们建议定义RipA的功能，它是一种在Francisella中保守的细胞质膜蛋白，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突变表型的基因外抑制因子的遗传和表型分析，鉴定RIPA结合蛋白，对RIPA拓扑和结构的生物物理研究，以及对RIPA表达的调控来实现。 公共卫生相关性：我们专注于了解图拉氏方济氏菌的细菌特性，这些特性使这种微生物成为对人类如此高毒力的病原体，特别是在肺部疾病方面。在这项应用中，我们将研究有限数量的弗氏杆菌特有的细胞成分的生物学特性，并确定它们对弗氏杆菌毒力和致病作用的贡献。

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.