The Role of IFI35 in Innate Immunity and Influenza Pathogenesis

项目摘要 流感病毒是一种重要的人类病原体，可导致人类严重疾病和死亡。高度 致病性流感病毒，如H5 N1，诱导过度的宿主反应， 炎性细胞因子的产生、先天免疫细胞的募集和适应性免疫的减弱 反应参与这种致病反应的宿主蛋白质在很大程度上是未知的。该信息 重要的，并将提供一个框架，合理设计新的治疗方法，对致病性流感 感染 我们先前已经鉴定了干扰素诱导蛋白35（IFI 35）作为与以下相关的宿主基因： 对高致病性H5 N1甲型流感病毒的易感性（2，3）。我们现在提供的数据显示 小鼠IFI 35与流感病毒诱导的疾病恶化之间的关系。IFI 35基因敲除小鼠感染 高致病性H5 N1流感病毒与同类野生型小鼠相比恢复更快， 产生较少的促炎细胞因子，如IL 12 p40、G-CSF和KC。相应地，骨髓 来源于IFI 35基因敲除小鼠的巨噬细胞在用抗IL-12抗体刺激后产生显著更少的IL-12 p40。 TLR 3激动剂。IL 12 p40作为同二聚体（IL 12 p402）产生，其是化学引诱剂和前趋化剂。 炎性细胞因子总之，IFI 35似乎是以下炎症反应的关键调节因子： 病毒感染该提议旨在表征IFI 35蛋白如何调节IL 12 p40和IL 12 p402 流感病毒感染后的产生，并研究IFI 35如何形成炎性 环境和疾病的结果。

PROJECT SUMMARY Influenza virus is an important human pathogen that can cause severe disease and death in humans. Highly pathogenic influenza viruses, such as H5N1, induce excessive host responses associated with pro- inflammatory cytokine production, recruitment of innate immune cells and a diminished adaptive immune response. The host proteins involved in this pathogenic response are largely unknown. This information is important and will provide a framework for the rational design of new treatments against pathogenic influenza infection. We have previously identified interferon induced protein 35 (IFI35) as a host gene associated with susceptibility to highly pathogenic H5N1 influenza A virus (2, 3). We now present data showing a direct link between murine IFI35 and exacerbation of influenza-virus induced disease. IFI35 knockout mice infected with the highly pathogenic H5N1 influenza virus recovered more rapidly compared to congenic wild type mice, producing less pro-inflammatory cytokines, such as IL12p40, G-CSF and KC. Correspondingly, bone marrow macrophages derived from IFI35 knockout mice produced significantly less IL12p40 following stimulation with a TLR3 agonist. The IL12p40 is produced as a homodimer (IL12p402) which is a chemo attractant and pre- inflammatory cytokine. In summary, IFI35 appears to be a key regulator of the inflammatory response following viral infection. This proposal is aimed at characterizing how IFI35 protein modulates IL12p40 and IL12p402 production after influenza virus infection and investigating mechanistically how IFI35 shapes the inflammatory environment and disease outcome.