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，在针对生物恐怖主义潜在因子的呼吸免疫发展中，宿主和微生物因素对先天性和适应性免疫的调节。该计划项目的共同重点是：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程度与随后的适应性反应联系起来; 3）细胞因子在控制先天和适应性反应中的作用; 4）树突细胞成熟和功能的调节;以及5）调节TLR信号传导对产生针对Y的保护性免疫的影响。鼠疫和痘病毒。这些领域的背景下，评估鞭毛蛋白，一种新的佐剂，两种病毒疫苗载体，SV 5和VSV，以及牛痘病毒抑制CD 8 + T细胞反应的机制进行了探讨。在项目1中，我们将确定TLR激动剂鞭毛蛋白的佐剂作用的机制，并建立其用于开发针对Y的保护性呼吸免疫应答的最佳条件。鼠疫和痘病毒。在项目2中，我们将研究病毒疫苗载体，副粘病毒猴病毒5（SV 5），在促进对Y。鼠疫和痘病毒，以及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，我们将定义水泡性口炎病毒的特征，这些特征涉及病毒的嗜神经性，并确定那些对促进对Y的先天性和适应性呼吸免疫的最佳水平至关重要的元素。鼠疫和痘病毒。项目4的研究将研究鼻内滴注牛痘病毒抑制小鼠CD 8 + T细胞应答的机制。这些研究将解决病毒对肺中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;和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.