Leukotrienes in Innate and Adaptive Antiviral Immunity

描述(申请人提供)：病毒感染在人类中造成广泛的死亡和疾病。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反应的细胞和分子机制。抗病毒免疫反应由先天的和适应性的成分组成。在缺乏有效的先天抗病毒反应的情况下，随后的适应性反应的效力就会变得迟钝。先天炎症免疫反应的一个主要组成部分是释放生物活性的花生四烯酸代谢产物介体，包括白三烯。白三烯既可以调节可减缓病毒复制的局部炎症反应，也可以调节抗原提呈细胞的迁移，这些细胞对启动高效的适应性抗病毒反应至关重要。对成功产生保护性抗病毒免疫反应所涉及的过程的了解是不完整的，而对白三烯在启动先天和适应性反应中的作用的理解是不完整的。到目前为止，这些先天炎症介质在启动保护性抗病毒免疫反应中的作用尚不清楚。我们目前的目标是研究白三烯在启动针对病毒感染的先天和获得性免疫反应中的作用。我们研究中的假设是，白三烯除了在刺激携带抗原的细胞外流，然后能够刺激产生抗病毒的T细胞反应之外，还起到了降低皮肤病毒感染严重程度的作用。为了实现这一目标，提出了三个具体目标：(I)确定半胱氨基白三烯在痘苗病毒皮肤感染后炎症中的作用；(Ii)确定白三烯在真皮病毒感染后浆细胞样树突状细胞分布和功能中的作用；(Iii)确定半胱氨基白三烯在病毒感染真皮部位的抗原运输到淋巴结以及随后的T细胞激活中的作用。这项拟议研究的基本原理是，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设计至关重要。在这个项目完成后，我们将有望确定白三烯调节先天和获得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.