Tularemia and the Human Innate Immune Response

兔热病和人类先天免疫反应

• 批准号: 6908198
• 负责人: GARY R. KLIMPEL
• 金额: $ 37.75万
• 依托单位: UNIVERSITY OF TEXAS MED BR GALVESTON
• 依托单位国家: 美国
• 财政年份: 2004
• 资助国家: 美国
• 起止时间: 2004-07-01 至 2009-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/6908198
• 关键词: Francisella tularensis; T lymphocyte; alveolar macrophages; bacterial proteins; bioterrorism /chemical warfare; cell population study; clinical research; cytokine; dendritic cells; diagnostic respiratory lavage; enzyme linked immunosorbent assay; flow cytometry; gene expression; genetic strain; human subject; immune response; immunity; live vaccine; microorganism growth; natural killer cells; tissue /cell culture; tularemia

DESCRIPTION (provided by applicant): Francisella tularensis is a gram-negative bacterium recently identified as one of the top-priority agents ("Class A") most likely to pose a potential risk to national security, Although much has been learned from a mouse model using an attenuated strain of Francisella, Francisella tularensis live vaccine strain (LVS), little is currently known about the human immune response to this bacterium. The overall goal of this proposal is gain a better understanding of how different cell populations of the human innate immune system respond to Francisella tularensis. We propose the following hypotheses. LVS and virulent Francisella induce different innate immune responses. Bacterial components other than LPS are important for activating cells of the innate immune response. Three specific aims are proposed to test these hypotheses: 1) Investigate the in vitro response(s) of human peripheral blood mononuclear cells (PBMC) following exposure to F. tularensis versus LVS, 2) Investigate human monocytes and dendritic cells (DC) for their responsiveness to virulent F. tularensis versus LVS, and 3) Investigate human TCRgd T cell and NK cell responses to virulent F. tularensis versus LVS. These specific aims will: a.) Identify the cytokines and cytokine-producing cells present in PBMC cultures following exposure to virulent F. tularensis versus LVS, b) Identify the cell populations that are expanded/activated following in vitro exposure to virulent F. tularensis versus LVS, c) Investigate whether human monocytes and/or DC respond differently to virulent F. tularensis versus LVS, d) Investigate whether is there a difference between virulent Francisella versus LVS with regard to their susceptibility to monocyte versus DC killing, e) Identify the bacterial components that can activate PBMC, monocytes, DCs, NK cells, and/or TCRgd T cells, and f) Investigate whether NK cells and/or TCRgd T cells kill virulent F. tularensis versus LVS. A full understanding of how the innate immune response reacts to Francisella will be extremely important for not only developing a successful vaccine for this pathogen, but also for furthering our understanding of how this bacterium is recognized by the human immune response.

描述(由申请人提供)：图拉方济氏菌是一种革兰氏阴性细菌，最近被确定为最有可能对国家安全构成潜在威胁的最优先病原体之一(A类)，尽管已经从使用图拉方济氏菌减毒株图拉氏方济氏菌活疫苗株(LVS)的小鼠模型中学到了很多东西，但目前对人类对这种细菌的免疫反应知之甚少。这项建议的总体目标是更好地了解人类先天免疫系统的不同细胞群如何对土拉氏方济各氏菌做出反应。我们提出了以下假设。金黄色葡萄球菌和强毒弗氏杆菌可诱导不同的先天免疫反应。细菌成分，而不是脂多糖，对于激活细胞的先天免疫反应很重要。为了验证这些假说，我们提出了三个特定的目标：1)研究人外周血单个核细胞对土拉氏F·S毒株的体外反应(S)；2)调查人单核细胞和树突状细胞(DC)对图拉氏F·L·S毒株的反应性；3)研究人TCRgd T细胞和NK细胞对F·tularensis与L V S毒力的反应。这些具体目标将：a.)鉴定毒力土拉氏菌与LVS暴露后PBMC培养中存在的细胞因子和细胞因子产生细胞，b)鉴定在体外暴露于毒力土拉氏菌与LVS后扩增/激活的细胞群，c)调查人类单核细胞和/或DC对毒力土拉氏菌与LVS的反应是否不同，d)调查毒力弗朗西斯菌与LVS在单核细胞对DC杀伤的敏感性方面是否存在差异，e)确定能够激活PBMC、单核细胞、DC、NK细胞和/或TCRgd T细胞的细菌成分，以及f)研究NK细胞和/或TCRgd T细胞是否杀死毒力较强的图拉氏丝虫而不是金黄色葡萄球菌。充分了解先天性免疫反应是如何对Francisella做出反应的，不仅对于开发成功的这种病原体疫苗非常重要，而且对于进一步了解这种细菌是如何被人类免疫反应识别的也是极其重要的。