Respiratory Immunity Against Agents of Bioterrorism

描述（由申请人提供）：本项目申请的中心主题是宿主和微生物因子对先天免疫和适应性免疫的调节，以发展呼吸道免疫以对抗潜在的生物恐怖主义因子。该方案项目有一个共同的重点：1)对鼠疫耶尔森氏菌和痘病毒的呼吸道免疫；2)将先天反应的质量或强度与随后的适应性反应联系起来；3)细胞因子在先天和适应性反应控制中的作用；4)树突状细胞成熟和功能的调控；5)调节TLR信号对鼠疫杆菌和痘病毒保护性免疫产生的影响。这些领域在评估鞭毛蛋白、一种新型佐剂、两种病毒疫苗载体SV5和VSV以及痘苗病毒抑制CD8+ T细胞反应的机制的背景下进行了探讨。在项目1中，我们将确定TLR激动剂鞭毛蛋白的佐剂作用机制，并确定其用于开发针对鼠疫杆菌和痘病毒的保护性呼吸道免疫反应的最佳条件。在项目2中，我们将研究病毒疫苗载体副粘病毒类猴病毒5 （SV5）促进对鼠疫菌和痘病毒的适应性免疫的机制和效果，并分析在病毒基因组背景下表达特异性TLR激动剂的效果。在项目3中，我们将定义水疱性口炎病毒的特征，这些特征与病毒的嗜神经性有关，并确定那些对于促进对鼠疫杆菌和痘病毒的先天和适应性呼吸免疫达到最佳水平至关重要的因素。项目4的研究将探讨鼻内灌注牛痘病毒抑制小鼠CD8+ T细胞反应的机制。这些研究将探讨病毒对肺部抗牛痘反应的先天和适应性阶段的潜在影响：树突状细胞的成熟和功能；细胞因子环境；细胞毒性T细胞功能；T细胞的能量和缺失。

DESCRIPTION (provided by applicant): This Program Project application has as its central theme, modulation of innate and adaptive immunity by host and microbial factors in the development of respiratory immunity against potential agents of bioterrorism. The Program projects share a common focus on 1) respiratory immunity to Yersinia pestis and poxviruses; 2) relating the quality or magnitude of an innate response to those in subsequent adaptive response; 3) the role of cytokines in the control of innate and adaptive responses; 4) the regulation of dendritic cell maturation and function; and 5) the impact of modulating TLR signaling on the generation of protective immunity to Y. pestis and poxviruses. These areas are explored in the context of assessing flagellin, a novel adjuvant, two viral vaccine vectors, SV5 and VSV, and the mechanism by which vaccinia virus suppresses the CD8+ T cell response. In Project 1, we will determine the mechanims(s) for the adjuvant effect of the TLR agonist, flagellin, and establish optimal conditions for its use in the development of protective respiratory immune responses against Y. pestis and poxviruses. In Project 2, we will investigate the mechanisms and efficacy of a viral vaccine vector, paramyxovirus simian virus 5 (SV5), in the promotion of adaptive immunity against Y. pestis and poxviruses, as well as analyze the effect of expressing specific TLR agonists in the context of the viral genome. In Project 3, we will define the features of vesicular stomatitis virus that are involved in the neurotropism of the virus and determine those elements that are essential for the promotion of an optimal level of innate and adaptive respiratory immunity to Y. pestis and poxviruses. The studies in Project 4 will investigate the mechanism by which intranasally instilled vaccinia virus suppresses the CD8+ T cell response in mice. These studies will address potential effects of the virus on the innate and adaptive phases of the anti-vaccinia response in the lung: the maturation and functions of dendritic cells; the cytokine environment; cytotoxic T cell function; and T cell anergy and deletion.