Toll-Like Receptors and Immunity to F. tularensis

项目3描述（由申请人提供）：土拉热弗朗西斯菌是革兰氏阴性菌， 土拉菌是一种细菌，是土拉菌病的病原体，土拉菌病是一种高度传染性疾病， 人类，尤其是肺炎型。F.土拉热菌是一种理想的生物武器， LD 50极低，易于气溶胶传播。如果早期诊断，这种疾病可以用抗生素治疗，但目前没有获得许可的疫苗，因此，如果大规模接触，人口将面临相当大的风险。许多研究集中在对来自F.土拉热亚种全北极圈，但几乎没有什么是已知的免疫反应，在肺炎土拉菌引起的高毒力F。土拉热亚种土拉热。Toll样受体（TLR）是关键的先天免疫应答元件，其通过识别由许多病原体表达的分子中的保守重复模式而充当第一道防线。TLR通过诱导趋化因子、促炎细胞因子和共刺激分子的表达来向先天性应答的细胞发出信号并形成随后的适应性免疫，因此是新佐剂和疫苗的重要靶标。我们的初步研究表明，在感染F.图拉热菌LVS的感染和MyD 88-/-和TLR 2-/-小鼠对LVS感染的易感性增加。最近 研究表明，F.土拉菌可以逃避宿主的先天免疫应答。这项工作的中心假设是TLR信号的激活/抑制在决定肺对强毒F.土拉热。拟议的研究将在小鼠肺炎土拉菌病的气溶胶感染模型中检验这一假设。我们将1）确定TLR信号传导在宿主对肺部感染F。土拉热亚种土拉菌（Schu 4）; 2）鉴定和表征TLR调节的免疫效应机制，其参与对肺土拉菌的先天性应答;和3）定义TLR信号调节机制，通过其F.土拉菌逃避宿主的先天免疫应答。我们希望这些研究将为我们理解强毒F的整体免疫发病机制提供重大进展。Toll样受体在宿主对肺炎土拉菌的先天性反应中的作用提供了重要的见解。

PROJECT 3 DESCRIPTION (provided by applicant): Francisella tularensis is a gram-negative bacterium that is the causative agent of tularemia, a highly infectious disease that can be fatal in humans, particularly in the pneumonic form. F. tularensis is an ideal bioweapon because of its extremely low LD50 and ease of aerosol dissemination. The disease is treatable with antibiotics if diagnosed early, but there is no licensed vaccine currently available and, therefore the population is at considerable risk in case of mass exposure. Many studies have focused on immunity to an attenuated live vaccine strain (LVS) derived from F. tularensis subsp. holoarctica, but virtually nothing is known about the immune response during pneumonic tularemia caused by the highly virulent F. tularensis subsp. tularensis. Toll-like receptors (TLRs) are critical innate immunity response elements that serve as a first line of defense by recognizing conserved, repeated patterns in molecules expressed by many pathogens. TLRs signal cells of the innate response and shape subsequent adaptive immunity by inducing expression of chemokines, pro-inflammatory cytokines and co-stimulatory molecules and thus are important targets for new adjuvants and vaccines. Our preliminary studies demonstrate a defect in the ability of primary alveolar macrophages from MyD88 mice to secrete TNF-a upon infection with F. tularensis LVS and increased susceptibility of MyD88-/- and TLR2-/- mice to LVS infection. Recent published studies suggest that F. tularensis may evade host innate immune responses. The central hypothesis for the proposed work is that activation/inhibition of TLR signaling plays a critical role in determining the nature of the innate response in the lung to aerosol infection by virulent F. tularensis. The proposed studies will test this hypothesis in an aerosol infection model of pneumonic tularemia in the mouse. We will 1) determine the role of TLR signaling in the host response to pulmonary infection with F. tularensis subsp. tularensis (Schu4) using KO mice and SiRNA; 2) identify and characterize TLR-regulated immune effector mechanisms that are involved in the innate response to pulmonary tularemia; and 3) define TLR signal-modulating mechanisms by which F. tularensis evades the host innate immune response. We expect that these studies will provide significant advances in our understanding of the overall immunopathogenesis of virulent F. tularensis and will provide critical insight into the role of Toll-like receptors in the host innate response to pneumonic tularemia.