高致病性流感病毒逃逸宿主固有免疫清除作用的机制研究

Severe Influenza infection usually is associated with hypercytokinemia, but the type I Interferon remains at low lever or absence. The regulatory mechanism on type I interferon by virus remains to be determined. We plan to explore two different approaches to unfold the underlying mechanism. First, we will investigate the traditional pattern recognition receptors and their signaling pathways, and determine how viral products will cause the unbalanced immune responses with preferentially up-regulating inflammatory cytokines but not type I interferon. The investigation will be performed on the lung tissues with a combo of technologies, including in situ hybridization and immunofluorescence staining and in situ interference with siRNA. In combination with in vitro experiments on cell lines, observations from these experiments will allow us to understand whether influenza virus are capable of attacking various targets in the IFN signaling pathway. Second, we will determine whether influenza is able to initiate an “emergence mode” or this mechanism is only initiated during hypoxia which could be resulted from the inflammation of lung by infection. Our studies may identify more targets for new drug development or immune intervention.

重症流感（如H7N9与H5N1）感染可诱导高水平炎症因子应答，但干扰素应答较低甚至缺失。病毒如何逃逸宿主干扰素通路的抑制作用尚未得到阐明。本研究从两条思路入手：一是以传统的模式识别受体及信号通路的调控为切入点，以体内肺组织原位观察病毒对信号通路的调控作用以及体内干扰特定靶标分子为主要手段，结合体外细胞模型进行验证，了解重症流感病毒对干扰素通路上的三个环节的是否均存在逃逸及其机制；二是探索重症流感感染是否启动宿主应急机制、或者感染导致的缺氧启动宿主应急机制、从而导致宿主产生高炎症因子应答，这一机制中表观调控起着决定性作用。这些机制的阐明为新药与免疫干预技术提供新的可能靶点。

流感病毒的致病性不仅与病毒毒力相关，更与宿主免疫反应相关。然而，宿主的抗流感免疫保护机制还不明晰。本研究通过转录组芯片分析、原位定量分析、体内干预、单细胞测序等技术解析流感病毒感染的重症化机制：1. I类干扰素应答为第一道免疫保护防线，其缺陷导致不能协同药物有效抑制病毒复制，病毒复制导致炎症因子风暴，致患者肺高度炎性侵润与实变。IFN-κ与抑炎分子TFF2，SOCS5均能有效提升宿主的生存，我们进一步解析了IFN-κ，TFF2与SOCS5的保护作用机制。这也提示我们，在重症流感感染的治疗策略上，除了抗病毒药物治疗外，“药物+干扰素+抑炎”可能为最佳方案；2. 流感特异性的CD8+T细胞应答出现越早(显著的克隆扩增)，康复越快，即流感特异性的CD8+T细胞应答可提供有效的保护，为宿主的第二道防护线；3. 有效的中和抗体应答是感染者获得生存的第三道防护线，也是最后一道防护线，而序贯免疫可作为诱导广谱交叉中和抗体反应的疫苗策略。本项目的研究不仅揭示了流感病毒感染过程中的宿主免疫保护机制，也为流感疫情的防控提供理论基础及新的潜在干预手段。

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