Role of dendritic cells in lethal H5N1 influenza infection

描述(申请人提供)：被甲型流感病毒大流行毒株以及目前流行的H5N1禽流感毒株感染导致高致死率，主要是由于促炎细胞因子/趋化因子在细胞渗透之前过度积累。为了对抗与感染相关的过度炎症，彻底了解肺内单个核细胞运输和树突状细胞生物学的潜在机制是至关重要的。这项提议将检验这样一种假设，即肺内单个核细胞运输和/或树突状细胞调节失调导致感染致死性H5N1流感病毒株导致的高病理学。在这项研究中，将描述感染后单个核细胞从骨髓运输到肺的动力学、表型和分化。这些数据将被用来确定致死性和亚致死性感染之间先天激活过程中的关键差异。利用肺中缺乏树突状细胞积累的基因敲除小鼠(CCR2-/-)，将检测树突状细胞对宿主病理和病毒清除的特定贡献。具体地说，这些实验将侧重于病毒的直接清除、病毒感染细胞的杀灭以及感染部位的抗原呈递。通过这些实验获得的知识将为开发有针对性的治疗方法奠定必要的基础，以减少过度炎症，而不损害清除病毒所需的免疫机制。过度炎症导致宿主病理增加，通常是死亡。此外，涉及单个核细胞从骨髓转运的机制并不只是流感感染的内在机制。从这些实验中获得的信息还可能提供对其他病原体感染、抗癌免疫以及自身免疫紊乱的洞察。

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.