Immune Evasion by F. tularensis

土拉弗朗西斯菌的免疫逃避

• 批准号: 7727737
• 负责人: JEFFREY Allen FRELINGER
• 金额: $ 37万
• 依托单位: UNIV OF NORTH CAROLINA CHAPEL HILL
• 依托单位国家: 美国
• 财政年份: 2009
• 资助国家: 美国
• 起止时间: 2009-07-22 至 2010-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7727737
• 关键词: Aerosols; Antigen Presentation; Bacteria; Biological; Cells; Data; Development; Dinoprostone; Dose; Down-Regulation; Environment; Francisella tularensis; Genes; Genetic; Goals; Growth; Histocompatibility Antigens Class I; Immune; Immune response; Immune system; Immunity; Immunologics; Infection; Kinetics; MHC Class I Genes; Mammals; Maps; Molecular; Molecular Genetics; Organism; Peptides; Process; Production; Proteins; Resistance to infection; Signal Pathway; T-Lymphocyte; Time; Vaccine Adjuvant; Viral; Virus; War; Work; antigen processing; base; in vivo; insight; macrophage; molecular site; pathogen; protein expression; public health relevance; research study; response; therapeutic vaccine; Aerosols; Antigen Presentation; Bacteria; Biological; Cells; Data; Development; Dinoprostone; Dose; Down-Regulation; Environment; Francisella tularensis; Genes; Genetic; Goals; Growth; Histocompatibility Antigens Class I; Immune; Immune response; Immune system; Immunity; Immunologics; Infection; Kinetics; MHC Class I Genes; Mammals; Maps; Molecular; Molecular Genetics; Organism; Peptides; Process; Production; Proteins; Resistance to infection; Signal Pathway; T-Lymphocyte; Time; Vaccine Adjuvant; Viral; Virus; War; Work; antigen processing; base; in vivo; insight; macrophage; molecular site; pathogen; protein expression; public health relevance; research study; response; therapeutic vaccine

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.

描述（由申请人提供）：该提案的目的是了解F. tularensis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。 F. tolarensis是一种革兰氏阴性菌，细胞内细菌。该细菌仅需通过气溶胶感染即可非常低的感染剂量，并且在环境中的寿命很长。尽管在美国的t藻菌感染并不高于高度普遍，但它有可能成为重要的病原体，尤其是在故意释放之后。虽然对F. tularensis的免疫反应尚未得到很好的研究，但它确实需要T细胞清除感染和抗性。我们的初步工作表明，与许多病毒和某些细菌一样，F。tularensis发展了多种逃避宿主先天和适应性免疫反应的策略。其中两个是，被感染的宿主细胞的PGE2产生以及感染细胞I类MHC I类的下调是该提案中研究的目标。在此应用中，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崛起以来，宿主和入侵者之间的战争一直持续。这种相互作用在细胞内细菌和哺乳动物之间的关系中已被磨练。先天性和适应性哺乳动物免疫系统的主要目的是避免由于细菌和病毒生长而破坏宿主。同时，细菌和病毒已经发展出多种机制以逃避宿主免疫反应。在这里，我们研究了细胞内病原体F. toarlensis进化的机制，以修饰宿主免疫反应，以使细菌能够更加生存和繁殖。对宿主与这些细菌的相互作用的研究将不仅有助于指出F. tularensis使用的机制，还可以指出其他病原体避免宿主免疫反应的方式。所使用的分子将提供有关有效免疫机制的重要见解，并为开发治疗剂和疫苗佐剂提供了潜在的可药物靶标。