Tularemia and the Human Innate Immune Response

兔热病和人类先天免疫反应

• 批准号: 7078594
• 负责人: GARY R. KLIMPEL
• 金额: $ 36.86万
• 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/7078594
• 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）：土拉热弗朗西丝氏菌是一种革兰氏阴性细菌，最近被鉴定为最有可能对国家安全构成潜在风险的最高优先级病原体之一（“A类”）。尽管已经从使用弗朗西丝氏菌减毒株（土拉热弗朗西丝氏菌活疫苗株（LVS））的小鼠模型中了解了很多，但目前对该细菌的人体免疫应答知之甚少。该提案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弗朗西斯菌作出反应。我们提出以下假设。LVS和强毒弗朗西斯菌诱导不同的先天免疫应答。除了LPS之外的细菌组分对于激活先天免疫应答的细胞是重要的。提出了三个具体目标来验证这些假设：1）研究人外周血单核细胞（PBMC）暴露于F后的体外反应。2）研究人单核细胞和树突状细胞（DC）对强毒F. 3）研究人TCRgd T细胞和NK细胞对强毒F.土拉菌与LVS的比较。这些具体目标将：（a）鉴定暴露于强毒F.土拉菌相对于LVS，B）鉴定在体外暴露于毒性F. c）研究人单核细胞和/或DC是否对毒性F.土拉热菌与LVS，d）研究毒性弗朗西斯菌与LVS之间在它们对单核细胞与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细胞的细菌组分，和f）研究NK细胞和/或TCRgd T细胞是否杀伤毒性弗朗西斯菌。土拉菌与LVS的比较。全面了解先天免疫反应如何对弗朗西斯菌作出反应，不仅对于开发针对该病原体的成功疫苗非常重要，而且对于进一步了解该细菌如何被人类免疫反应识别也非常重要。