Respiratory Immunity Against Agents of Bioterrorism

描述(由申请人提供)：本计划项目申请的中心主题是宿主和微生物因素在呼吸道免疫发展中对潜在生物恐怖主义因素的调节。该计划的共同重点是：1)对鼠疫和痘病毒的呼吸道免疫；2)先天反应的质量或大小与随后的适应性反应有关；3)细胞因子在控制先天和适应性反应中的作用；4)树突状细胞成熟和功能的调节；以及5)调节TLR信号对产生对鼠疫和痘病毒的保护性免疫的影响。这些领域是在评估鞭毛蛋白，一种新的佐剂，两种病毒疫苗载体，SV5和VSV，以及牛痘病毒抑制CD8+T细胞反应的机制的背景下探索的。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(S)，并建立其用于开发针对鼠疫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猴病毒5(SV5)在促进针对鼠疫和痘病毒的适应性免疫中的机制和有效性，并分析在病毒基因组的背景下表达特定的TLR激动剂的效果。在项目3中，我们将定义水泡性口炎病毒的特征，这些特征与病毒的神经亲和性有关，并确定那些对促进对鼠疫和痘病毒的天然和适应性呼吸道免疫的最佳水平至关重要的要素。项目4中的研究将探讨鼻腔注射痘苗病毒抑制小鼠CD8+T细胞反应的机制。这些研究将讨论病毒对肺内抗痘苗反应的先天和适应阶段的潜在影响：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；以及T细胞无能和缺失。

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.