Tularemia and the Human Innate Immune Response

兔热病和人类先天免疫反应

• 批准号: 6827541
• 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/6827541
• 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）：土拉菌弗朗西斯菌是一种革兰氏阴性菌，最近被确定为最可能对国家安全构成潜在风险的顶级药物（“a类”）之一，尽管使用弗朗西斯菌的减毒菌株，土拉菌弗朗西斯菌活疫苗菌株（LVS）的小鼠模型已经了解了很多，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菌做出反应。我们提出以下假设。LVS和强毒Francisella诱导不同的先天免疫反应。除脂多糖外，细菌成分对激活先天免疫反应的细胞很重要。我们提出了三个特定的目的来验证这些假设：1)研究暴露于土拉菌与LVS后人外周血单个核细胞（PBMC）的体外反应，2)研究人单核细胞和树突状细胞（DC）对强毒土拉菌与LVS的反应，3)研究人TCRgd T细胞和NK细胞对强毒土拉菌与LVS的反应。这些具体目标将：a)；鉴定暴露于毒力土拉菌与LVS后PBMC培养物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菌与LVS后扩增/激活的细胞群，c)研究人类单核细胞和/或DC对毒力土拉菌与LVS的反应是否不同。d)研究致病性Francisella与LVS在单核细胞与DC杀伤的易感性方面是否存在差异；e)鉴定可以激活PBMC、单核细胞、DC、NK细胞和/或TCRgd T细胞的细菌成分；f)研究NK细胞和/或TCRgd T细胞是否能杀死致病性tularensis与LVS。充分了解先天免疫反应如何对弗朗西斯菌作出反应，不仅对开发成功的针对这种病原体的疫苗非常重要，而且对进一步了解这种细菌是如何被人体免疫反应识别的也非常重要。