Leukotrienes in Innate and Adaptive Antiviral Immunity

描述（由申请方提供）：病毒感染导致人群广泛死亡和疾病。我们计划的长期目标是确定参与产生有效保护性抗病毒免疫应答的细胞和分子机制。抗病毒免疫反应由先天性和适应性组成。在缺乏有效的先天性抗病毒应答的情况下，随后的适应性应答的功效被削弱。先天性炎性免疫应答的主要成分是生物活性花生四烯酸代谢物介质（包括白三烯）的释放。白三烯可以介导可减缓病毒复制的局部炎症反应和抗原呈递细胞的迁移，这对于启动有效的适应性抗病毒反应至关重要。关于成功产生保护性抗病毒免疫应答的过程的知识是不完整的，因为理解了白三烯在先天性和适应性应答的启动中的作用。迄今为止，这些先天性炎症介质在启动保护性抗病毒免疫应答中的作用尚不清楚。我们目前的目标是研究白三烯在启动先天性和适应性免疫反应的病毒感染的作用。我们研究中的假设是，除了它们在刺激携带抗原的细胞的外流中的作用之外，白三烯还起到降低皮肤中病毒感染的严重程度的作用，所述细胞然后能够刺激产生性抗病毒T细胞应答。为了实现这一目标，提出了三个具体目标：（I）确定半胱氨酰白三烯在牛痘病毒皮肤感染后炎症中的作用;（II）确定白三烯在皮肤病毒感染后浆细胞样树突状细胞分布和功能中的作用;（III）确定半胱氨酰白三烯在抗原从病毒感染的皮肤部位转运至淋巴结以及随后的T细胞活化中的作用。这项研究的基本原理是，了解白三烯在抗病毒反应中的作用对于抗病毒药物和疫苗的基本原理设计至关重要。在这个项目完成后，我们将有望确定白三烯介导先天性和适应性抗病毒免疫的机制。

DESCRIPTION (provided by applicant): Viral infections cause widespread death and disease in the human population. The long-range goal of our program is to define the cellular and molecular mechanisms involved in the generation of an efficient protective antiviral immune response. An antiviral immune response is comprised of innate and adaptive components. In the absence of an effective innate antiviral response the efficacy of the subsequent adaptive response is blunted. A major component of the innate inflammatory immune response is the release of bioactive arachidonic acids metabolites mediators, including leukotrienes. Leukotrienes can mediate both the local inflammatory response that can slow virus replication, and the migration of antigen presenting cells that are vital for the initiation of a productive adaptive antiviral response. Knowledge of the processes involved in successful generation of a protective antiviral immune response is incomplete with an understanding of the role of leukotrienes in the initiation of innate and adaptive responses. To date, the role of these innate inflammatory mediators in initiation of a protective antiviral immune response is unknown. Our current objective is to examine the role leukotrienes in the initiation of both the innate and adaptive immune responses to virus infection. The hypothesis in our studies is that leukotrienes function to reduce the severity of a viral infection in the skin, in addition to their role in stimulating the exodus of antigen bearing cells that are then able to stimulate a productive antiviral T cell response. To achieve this objective, three specific aims are proposed: (I) To determine the role of cysteinyl leukotrienes in inflammation following dermal infection with vaccinia virus; (II) To determine the role of leukotrienes in plasmacytoid dendritic cell distribution and function following dermal virus infection and; (III) To determine the role of cysteinyl leukotrienes in the transport of antigen from a dermal site of virus infection to the lymph node, and subsequent T cell activation. The rationale for the proposed research is that an understanding of the role of leukotrienes in antiviral responses is critical for the rationale designs of antiviral drugs and vaccines. At the completion of this project we will expect to have identified the mechanisms by which leukotrienes mediate innate and adaptive antiviral immunity.