Immune Evasion by F. tularensis

描述（由申请人提供）：本提案的目标是了解土拉菌用于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。土拉菌是一种革兰氏阴性的兼性细胞内细菌。这种细菌通过气溶胶感染只需要非常低的感染剂量，并且在环境中具有很长的寿命。虽然土拉菌感染在美国不是很普遍，但它有可能成为一种重要的病原体，特别是在故意释放后。虽然对土拉菌病的免疫反应尚未得到很好的研究，但它确实需要T细胞来清除感染并抵抗再感染。我们的初步工作表明，像许多病毒和一些细菌一样，土拉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。其中感染的宿主细胞产生PGE2和感染细胞上MHC I类的下调是本课题研究的目标。在这个应用中，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：自从第一批多细胞生物出现以来，宿主和入侵者之间的战争就一直持续着。这种相互作用在细胞内细菌和哺乳动物之间的关系中已经达到了很高的水平。哺乳动物先天免疫系统和适应性免疫系统的主要目的都是避免因细菌和病毒的生长而破坏宿主。同时，细菌和病毒已经进化出多种机制来逃避宿主的免疫反应。本文研究了胞内病原菌土拉菌改变宿主免疫反应的机制，以使细菌更能生存和繁殖。研究宿主与这些细菌的相互作用不仅有助于指出土拉菌病的机制，而且有助于指出其他病原体避免宿主免疫反应的途径。所使用的分子将为有效免疫机制提供重要的见解，并为治疗方法和疫苗佐剂的开发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.