Ifitm3 Limits the Severity of Acute Influenza in Mice

Interferon-induced transmembrane (IFITM) proteins are a family of viral restriction factors that inhibit the entry processes of several pathogenic viruses, including influenza A virus (IAV), in vitro. Here we report that IAV-infected knockout mice lacking the Ifitm locus on chromosome 7 exhibited accelerated disease progression, greater mortality, and higher pulmonary and systemic viral burdens as compared to wild type controls. We further observed that the phenotype of Ifitm3-specific knockout mice was indistinguishable from that of mice lacking the entire Ifitm locus. Ifitm3 was expressed by IAV target cells including alveolar type II pneumocytes and tracheal/bronchial respiratory epithelial cells. Robust Ifitm3 expression was also observed in several tissues in the absence of infection. Among murine Ifitm promoters, only that of Ifitm3 could be induced by type I and II interferons. Ifitm3 could also be upregulated by the gp130 cytokines IL-6 and oncostatin M on cells expressing appropriate receptors, suggesting that multiple cytokine signals could contribute to Ifitm3 expression in a cell or tissue-specific manner. Collectively, these findings establish a central role for Ifitm3 in limiting acute influenza in vivo, and provide further insight into Ifitm3 expression and regulation.

干扰素诱导跨膜蛋白（Interferon-induced transmembrane, IFITM）是一类病毒限制因子家族，可在体外抑制包括甲型流感病毒（influenza A virus, IAV）在内的多种致病性病毒的入侵过程。本研究发现，与野生型对照组相比，经甲型流感病毒感染、缺失7号染色体Ifitm基因座的基因敲除小鼠表现出疾病进程加速、死亡率升高以及肺部和全身病毒载量更高的表型。我们进一步观察到，Ifitm3特异性基因敲除小鼠的表型与缺失完整Ifitm基因座的小鼠无显著差异。IAV的靶细胞包括肺泡II型上皮细胞以及气管/支气管呼吸道上皮细胞，此类细胞可表达Ifitm3。在未感染状态下的多种组织中，同样可检测到Ifitm3的显著高表达。在小鼠Ifitm基因的启动子中，仅Ifitm3的启动子可被I型和II型干扰素诱导激活。在表达相应受体的细胞中，gp130家族细胞因子白细胞介素6（Interleukin-6, IL-6）与制瘤素M亦可上调Ifitm3的表达，这提示多种细胞因子信号可通过细胞或组织特异性的方式参与Ifitm3的表达调控。综上，本研究确立了Ifitm3在体内限制急性流感病毒感染中的核心作用，并为Ifitm3的表达与调控机制提供了新的见解。