Tularemia: Pathogenesis and Host Response

描述(申请人提供)：图拉氏方济氏菌可导致人类严重疾病和死亡。由于容易通过雾化传播，以及与吸入性图拉热症相关的高发病率和死亡率，图拉氏丝虫被认为是最有可能的生物武器之一。目前还没有获得普遍使用许可的图拉热病疫苗，因此人类面临着非法使用图拉氏丝虫的重大风险。由于对图拉氏丝虫的致病机制和宿主反应知之甚少，因此对图拉氏丝虫生物学的基础研究对于未来图拉热病的治疗和疫苗的发展至关重要。我们从德克萨斯大学圣安东尼奥分校和圣安东尼奥的德克萨斯大学健康科学中心的研究人员那里收集了一组专注于方济各氏菌发病机制和免疫的综合研究项目。这些单独的项目被设计为与其他项目高度整合，并最终产生协同效应，将推动我们对这一潜在生物武器的了解，从而可以开发新的抗菌战略。对图拉氏丝孢子虫亚种的气溶胶感染几乎一无所知。图拉热病(A型)是最有可能的图拉热症的生物武器形式，因此该方案项目几乎完全集中在这种图拉热症上。我们的综合细菌学和免疫学研究方法涉及四个研究项目和三个支持核心。这些项目的目的是：1.鉴定图拉氏疟原虫的基本和毒力因子；2.详细介绍吸入性图拉热的免疫学；3.鉴定Toll样受体在宿主反应中的作用；4.鉴定T细胞表位并鉴定T细胞介导的对图拉氏杆菌的应答。这些项目将得到一个行政核心、一个基因组核心和一个免疫显微镜核心的支持。研究人员的协作互动最终将大大增加我们对图拉氏菌亚种病原菌-寄主相互作用的理解。图拉热病气雾剂感染，并促进新疗法和疫苗的开发，以对抗武器化图拉热症。

DESCRIPTION (provided by applicant): Francisella tularensis can cause serious illness and death in humans. F. tularensis is considered to be one of the most likely bioweapons due to ease of dissemination through aerosolization, and the high morbidity and mortality associated with inhalation tularemia. There is currently no tularemia vaccine licensed for general use, and thus human populations are at significant risk from the illicit use of F. tularensis. Very little is known about F. tularensis pathogenesis and host response, and thus fundamental research into F. tularensis biology is critical for the future development of therapeutics and vaccines against tularemia. We have assembled a group of integrated research projects focused on Francisella pathogenesis and immunity from researchers at the University of Texas San Antonio and the University of Texas Health Science Center in San Antonio. The individual projects are designed to be highly integrated with the other projects, and ultimately lead to a synergy that will propel our knowledge of this potential bioweapon such that new antimicrobial strategies can be developed. Virtually nothing is known about aerosol infections of F. tularensis subsp. tularensis (Type A), the most likely bioweapon form of tularemia, and thus this program project focuses almost exclusively on this form of tularemia. Our integrated bacteriological and immunological research approach involves four research projects and three support cores. These projects are designed to 1. identify essential and virulence factors of F. tularensis, 2. detail the immunology of inhalation tularemia in situ, 3. characterize the role of Toll-like receptors in host response, and 4. identify T cell epitopes and characterize T cell mediated responses to F. tularensis. These projects will be supported by an administrative core, a genomics core, and an immunomicroscopy core. The collaborative interactions of the investigators will ultimately lead to a dramatic increase in our understanding of pathogen-host interactions during F. tularensis subsp. tularensis aerosol infections, and facilitate the development of novel therapeutics and vaccines to combat weaponized tularemia.