Innate Immunity to Francisella tularensis

对土拉弗朗西斯菌的先天免疫

• 批准号: 7140492
• 负责人: MICHAEL J PARMELY
• 金额: $ 19.74万
• 依托单位: UNIVERSITY OF KANSAS MEDICAL CENTER
• 依托单位国家: 美国
• 财政年份: 2005
• 资助国家: 美国
• 起止时间: 2005-07-15 至 2008-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7140492
• 关键词: Francisella tularensis; antigen antibody reaction; bactericidal immunity; colony stimulating factor; enzyme linked immunosorbent assay; flow cytometry; host organism interaction; interferon gamma; laboratory mouse; leukocyte activation /transformation; macrophage; molecular shape; natural killer cells; toll like receptor

DESCRIPTION (provided by applicant): Francisella tularensis is a facultative intracellular gram-negative bacterium responsible for human tularemia. Interest in the pathogen has increased recently with the realization that it could be used as an agent of bioterrorism due to its high infectivity, potentially high mortality rates and the ability to deliver the organism to large numbers of persons by aerosol. Natural infections with F. tularensis proceed from an initial localized site via blood dissemination to the spleen, liver, lungs, CMS and kidneys. Immunity sufficient to resolve primary infections and mediate memory responses to secondary exposure is dependent on T cells, the cytokine interferon-gamma (IFN-g) and the activation of macrophages. However, relatively little is known about protective immune responses to primary infection that occur within the first week of exposure. Thus, it is not known which cells of the innate immune system respond to the bacterium, how they recognize microbial components or how they might initiate clearance. The long-term objective of this research is to characterize the cellular basis of IFN-g production during the initial phase of F. tularensis infection and define the mechanisms of immune recognition of the microbe in naive mice. Our central hypothesis is that IFN-g production by NK and NKT cells, which recognize the bacterium through their Toll-like receptors (TLR), is a key process in the early protective immunity. Our specific aims are to: (i) identify the cellular subsets that are activated for IFN-g production during F. tularensis infection; (ii) define the role of TLR and accessory signals in the induction of these responses; and (iii) determine the role of TLR-mediated NK and NKT cell activation in early clearance of F. tularensis. Besides providing important insight into the nature of innate immunity to F. tularensis, this R21 application will assess the participation of NK/NKT cells and TLR-mediated signaling in these protective responses and generate important preliminary data to characterize the role of these cells in immune protection during the first few days of infection.

描述（由申请人提供）：Francisella tuarlarensis是负责人to症的细胞内革兰氏阴性细菌。由于其高感染率，潜在的高死亡率以及通过气溶胶将生物传递给大量人的能力，人们对病原体的兴趣最近增加了，它可以用作生物恐怖主义的药物。 F. tularensis的自然感染是通过将血液传播到脾，肝脏，肺，CMS和肾脏从初始局部部位进行的。足以解决原发性感染并介导对继发暴露的记忆反应的免疫力取决于T细胞，细胞因子干扰素 - 伽马（IFN-G）和巨噬细胞的激活。但是，关于暴露后第一周发生的对原发性感染的保护性免疫反应相对较少。因此，尚不清楚先天免疫系统的哪些细胞对细菌的反应，它们如何识别微生物成分或如何启动清除率。这项研究的长期目的是表征在flaremensis感染的初始阶段IFN-G产生的细胞基础，并定义幼稚小鼠中微生物的免疫识别的机制。我们的中心假设是，NK和NKT细胞的IFN-G产生，这些细菌通过其Toll样受体（TLR）识别细菌，是早期保护性免疫的关键过程。我们的具体目的是：（i）确定在F. tularensis感染期间因IFN-G产生而激活的细胞子集； （ii）定义TLR和附件信号在诱导这些响应中的作用； （iii）确定TLR介导的NK和NKT细胞活化在F. tularensis的早期清除率中的作用。除了对f菌的先天免疫性质提供重要的见解外，该R21应用还将评估NK/NKT细胞和TLR介导的信号在这些保护性反应中的参与，并生成重要的初步数据，以表征这些细胞在感染的最初几天中这些细胞在免疫保护中的作用。

项目成果

Coactivating signals for the hepatic lymphocyte gamma interferon response to Francisella tularensis.

肝淋巴细胞γ干扰素对土拉弗朗西斯菌反应的共激活信号。

• DOI: 10.1128/iai.01203-06
• 发表时间: 2007
• 期刊: Infection and immunity
• 影响因子: 3.1
• 作者: Wickstrum,JasonR;Hong,Kee-Jong;Bokhari,Sirosh;Reed,Natalie;McWilliams,Nicholas;Horvat,RebeccaT;Parmely,MichaelJ
• 通讯作者: Parmely,MichaelJ

Francisella tularensis induces extensive caspase-3 activation and apoptotic cell death in the tissues of infected mice.

土拉弗朗西斯菌在受感染小鼠的组织中诱导广泛的 caspase-3 激活和细胞凋亡。

• DOI: 10.1128/iai.00246-09
• 发表时间: 2009
• 期刊: Infection and immunity
• 影响因子: 3.1
• 作者: Wickstrum,JasonR;Bokhari,SiroshM;Fischer,JeffreyL;Pinson,DavidM;Yeh,Hung-Wen;Horvat,RebeccaT;Parmely,MichaelJ
• 通讯作者: Parmely,MichaelJ

Programmed cell death and the pathogenesis of tissue injury induced by type A Francisella tularensis.

• DOI: 10.1111/j.1574-6968.2009.01791.x
• 发表时间: 2009-11
• 期刊: FEMS microbiology letters
• 影响因子: 2.1
• 作者: Parmely MJ;Fischer JL;Pinson DM
• 通讯作者: Pinson DM