Role of dendritic cells in lethal H5N1 influenza infection

描述（由申请人提供）：甲型流感病毒大流行毒株以及目前流行的H5N1禽流感毒株的感染导致高致死率，主要是由于细胞浸润前促炎细胞因子/趋化因子的过度积累。为了对抗与感染相关的过度炎症，深入了解肺内单个核细胞运输和树突状细胞生物学的机制是必不可少的。这一建议将验证一种假设，即肺内单核细胞运输的改变和/或树突状细胞的失调导致了致命的H5N1甲型流感病毒毒株感染导致的高病理学。在这项研究中，动力学，表型和单核细胞运输从骨髓到肺的分化将在感染后表征。这些数据将用于确定致死性和亚致死性感染之间先天激活过程的关键差异。使用敲除小鼠（CCR2-/-）缺乏树突状细胞在肺中的积累，树突状细胞对宿主病理和病毒清除的特异性贡献将被检查。具体来说，这些实验将侧重于直接清除病毒，杀死病毒感染的细胞，以及抗原在感染部位的呈递。通过这些实验获得的知识将为开发靶向治疗奠定必要的基础，以减少导致宿主病理增加和经常死亡的过度炎症，同时不损害病毒清除所需的免疫机制。此外，单核细胞从骨髓转运的机制不仅仅是流感感染所固有的。从这些实验中获得的信息也可能为其他病原体感染、抗癌免疫以及自身免疫疾病提供见解。

DESCRIPTION (provided by applicant): Infection by pandemic strains of influenza A virus, as well as the currently circulating H5N1 avian strains, results in a high rate of lethality, primarily due to the excessive accumulation of proinflammatory cytokines/chemokines that precedes cellular infiltration. In order to combat the excessive inflammation associated with infection, a thorough understanding of the mechanisms underlying mononuclear cell trafficking and dendritic cell biology within the lung is essential. This proposal will test the hypothesis that altered mononuclear cell trafficking and/or dysregulation of dendritic cells within the lung contribute to the high-pathology resulting from infection with lethal H5N1 strains of influenza A virus. In this study, the kinetics, phenotype, and differentiation of mononuclear cell trafficking from the bone marrow to the lung will be characterized following infection. These data will be used to determine critical differences in the course of innate activation between lethal and sublethal infections. Using a knockout mouse (CCR2-/-) deficient in dendritic cell accumulation in the lung, the specific contribution of dendritic cells to both host pathology and viral clearance will be examined. Specifically, these experiments will focus on direct viral clearance, killing of virus-infected cells, and antigen presentation at the site of infection. The knowledge gained by these experiments will lay the groundwork necessary for development of targeted therapies to reduce the excessive inflammation that contributes to increased host pathology and often death, without compromising the immune mechanisms required for viral clearance. Furthermore, the mechanisms involved in mononuclear cell trafficking from the bone marrow are not intrinsic to only influenza infection. The information gained from these experiments may also provide insight into infection by other pathogens, anti- cancer immunity, as well as auto-immune disorders.