Immune Evasion by F. tularensis

描述(申请人提供)：这项提案的目标是了解图拉氏F菌用来逃避免疫反应的策略，并最终设计出击败细菌免疫逃避的方法。图拉氏杆菌是一种革兰氏阴性兼性胞内细菌。这种细菌通过气溶胶感染只需要很低的感染量，并且在环境中有很长的寿命。虽然图拉氏丝虫在美国的感染不是很普遍，但它有可能成为一种重要的病原体，特别是在故意释放之后。虽然对图拉氏丝虫的免疫应答还没有得到很好的研究，但它确实需要T细胞来清除感染和抵抗再次感染。我们的初步工作表明，像许多病毒和一些细菌一样，图拉氏F菌已经进化出多种策略来逃避宿主的先天和适应性免疫反应。其中两个，受感染的宿主细胞产生PGE2和MHC I类分子对受感染细胞的下调是本提案中研究的目标。在这项应用中，我们建议了解这两种形式的免疫逃避的遗传和分子基础。公共卫生相关性：自第一批多细胞生物体出现以来，宿主和入侵者之间的战争一直持续着。这种相互作用在细胞内细菌和哺乳动物之间的关系中被磨练到了一个很高的水平。哺乳动物先天免疫系统和获得性免疫系统的主要目的都是避免由于细菌和病毒的生长而破坏宿主。与此同时，细菌和病毒进化出多种机制来逃避宿主的免疫反应。在这里，我们研究了细胞内病原菌图拉氏杆菌通过改变宿主的免疫反应来使细菌更能生存和繁殖的机制。研究寄主与这些细菌的相互作用不仅有助于指出图拉氏F菌所使用的机制，而且还有助于指出其他病原体避免宿主免疫反应的方式。所使用的分子将为有效免疫的机制提供重要的见解，并为治疗学和疫苗佐剂的发展提供潜在的可药物靶点。

DESCRIPTION (provided by applicant): The goal of this proposal is to understand the strategies used by F. tularensis to evade the immune response, and to ultimately devise ways to defeat the immune evasion by the bacteria. F. tularensis is a gram-negative, facultative intracellular bacterium. This bacteria require only a very low infective dose via aerosol infection, and has a long lifetime in the environment. Although F. tularensis infection in the US is not highly prevalent, it has the potential to become an important pathogen especially following intentional release. While the immune response to F. tularensis has not been well studied, it does require T cells for clearance of infection and resistance to reinfection. Our preliminary work shows that like many viruses and some bacteria, F. tularensis has evolved multiple strategies for evading the host innate and adaptive immune response. Two of these, the production of PGE2 by infected host cells and the down-regulation of MHC class I on infected cells are the targets for study in this proposal. In this application we propose to understand the genetic and molecular basis for these two forms of immune evasion. Public Health Relevance: The war between hosts and invaders has endured since the rise of the first multicellular organisms. This interaction has been honed to a high level in the relationship between intracellular bacteria and mammals. The main purpose of both the innate and adaptive mammalian immune systems is to avoid the destruction of the host due to bacterial and viral growth. At the same time bacteria and viruses have evolved multiple mechanisms to evade the host immune response. Here we study the mechanism evolved by the intracellular pathogen F. tularensis to modify the host immune response in order to make the bacteria more able to survive and multiply. The study of the interactions of the host with these bacteria will help point out not only the mechanism used by F. tularensis, but also ways in which other pathogens avoid the host immune response. The molecules used will provide important insights into the mechanisms of effective immunity, and provide potential drugable targets for the development of therapeutics, and vaccine adjuvants.