老年化进程中机体免疫功能逐渐衰退且抵御感染能力显著降低。典型案例为人感染新型高致病性禽流感病毒（HPAIs）H7N9，老年人易感且预后不佳。本团队前期发现H7N9感染可诱导老年体内高水平炎症因子（IL-6,IL-8及MIP-1b）并伴有IFITM3介导的I型IFN抗病毒通路损伤。.本课题将在前期构建的流感病毒（H3N2/H1N1/H7N9）成年小鼠感染模型基础上，建立老年小鼠H7N9感染模型。以H7N9感染的成年鼠为参照，分析H7N9感染老年小鼠与成年小鼠时，参与免疫应答如抗原提呈细胞与炎症活化的重要细胞群DCs, NK, T细胞与抗体应答的差异性；通过基因转录组学与表观遗传技术筛选NF-kB/I型IFN通路中差异化表达的分子（DE-genes），并在老年与成年人H7N9感染者的组织标本中加以印证。在小鼠肺组织动态定位炎症应答始动细胞与关键分子，随后在体外细胞水平验证关键分子对始动细胞的信号传导通路的调控作用，从而明确老年宿主H7N9感染导致偏向性诱导炎症应答的分子机制，并为老年病毒感染的免疫干预策略提供生物学靶点。

The aging results in the immunosenescence and becomes more vulnerable to infection, which is recently exemplified by H7N9 infection that causes more severe outcomes in clinic in elder patients. Our previous report showed H7N9 infection induced hypercytokinemia (such as IL-6, IL-8, and macrophage inflammatory protein-1β) especially in the aged patients with a minimal type I interferon response, the functional deficiency of IFITM3 further exacerbates the dysregulated immune responses. Based on our previous established animal influenza infection model in mice（H3N2/H1N1/H7N9）, we will further develop influenza infection model in aged mice. By employing the transcriptomic and Epigenomic tools, we will screen and identify the differentially expressed genes and miRNA between adult and aged mice after H7N9 infection. In parallel, we will also identify the differentially expressed genes and miRNA between H7N9-infected adults and elder subjects during natural H7N9 infection. The similarly regulated genes in both aged mice and aged human will be analyzed for their signaling pathways and the signaling pathway clustered with differentially expressed genes will be targeted for siRNA to knock down and to re-direct the dysregulated immune responses. The most influential genes and pathways will be identified as our targets. Meanwhile, the similarly up-regulated miRNA in elder mice and human will be selected for their functional analysis to determine their role in the dysregulated resposes. This study will unfold the basis for the development of new drugs and immune intervention strategies which could improve the health of aged individuals.