流感严重危害人类健康。前期研究发现流感病毒感染的重要特征是CD3+T为主的外周血淋巴细胞减低，流感病毒能够感染T淋巴细胞并在感染细胞内复制。然而，流感病毒如何感染T淋巴细胞并引起细胞异常死亡不清楚。相对淋巴细胞，流感病毒更易感染单核巨噬细胞，阻断单核巨噬细胞-淋巴细胞间黏附可成功阻断淋巴细胞感染；ZBP1是介导流感病毒感染上皮细胞死亡的主要分子。基于前期研究结果及文献报道，提出科研假说：流感病毒借助单核巨噬细胞与T淋巴细胞表面形成的病毒学突触感染T淋巴细胞，并在感染细胞内复制产生Z-RNA激活ZBP1介导淋巴细胞程序性死亡。为验证此假说，本项目将利用临床标本、多种实验动物模型、多类型重组病毒株，结合流式、Western Blotting、单细胞测序、激光共聚焦显微镜动态成像及扫描电镜技术，在组织、细胞、分子层面阐释流感病毒感染并引起T淋巴细胞死亡机制，为重症流感的药物研发提供新的思路。

Influenza infection poses a great threat to human health worldwide, characterized by the reduction of peripheral blood CD3+T lymphocytes. Our preliminary study revealed influenza virus could infect and replicate in T lymphocytes. However, how influenza virus infects T lymphocytes, then causes abnormal cell death and affects the lung's anti-influenza adaptive immune response remains undetermined currently. It is reported that monocytes-macrophages are relatively more susceptible to influenza virus infection compared to other immune cell types. Lymphocyte infection occurred in the context of immune cell clusters and was blocked by the addition of anti-intercellular adhesion molecule-1 antibody to prevent cell clustering. Early studies showed ZBP1 is the main molecule that mediates epithelial cell death during influenza virus infection. Based on our preliminary research results and literature reports, it is hypothesized that T lymphocytes could be infected by influenza virus via virological synapses formed between infected monocytes-macrophages and uninfected lymphocytes, and then Z-RNA produced during virus replication, binds to ZBP1 mediating programmed cell death, which in turn affects the lung's antiviral adaptive immune response. With flowcytomytry, Western Blotting, single-cell sequencing, laser confocal microscopy dynamic imaging and scanning electron microscopy techniques, the project will use clinical specimens, a variety of experimental animal models and multiple types of recombinant virus strains to validate these hypotheses. The current study will provide an in-depth and context-dependent understanding of the mechanism of T lymphocytes infected by influenza virus and cell death pathways during the progression of IAV infection, which may further allow us to better identify therapeutically beneficial targets that do not inadvertently increase disease pathogenicity.