Department of Microbiology and Immunobiology, Harvard Medical School, New England Primate Research Center, Southborough, Massachusetts, United States of America.
PLoS Pathog. 2012 Sep;8(9):e1002909. doi: 10.1371/journal.ppat.1002909. Epub 2012 Sep 6.
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（IFITM）蛋白家族是一类病毒限制因子，能够抑制多种致病性病毒的进入过程，包括甲型流感病毒（IAV）。本研究报道，与野生型对照相比，缺失染色体 7 上 Ifitm 基因座的 IAV 感染敲除小鼠表现出疾病进展加速、死亡率更高、肺部和全身病毒载量更高的现象。我们还观察到，Ifitm3 特异性敲除小鼠的表型与缺失整个 Ifitm 基因座的小鼠没有区别。Ifitm3 由 IAV 靶细胞表达，包括肺泡 II 型上皮细胞和气管/支气管呼吸上皮细胞。在没有感染的情况下，在几种组织中也观察到了强烈的 Ifitm3 表达。在鼠 Ifitm 启动子中，只有 Ifitm3 可以被 I 型和 II 型干扰素诱导。Ifitm3 还可以被表达适当受体的 gp130 细胞因子 IL-6 和肿瘤坏死因子 M 上调，这表明多种细胞因子信号可以以细胞或组织特异性的方式促进 Ifitm3 的表达。综上所述，这些发现确立了 Ifitm3 在限制体内急性流感中的核心作用，并进一步深入了解了 Ifitm3 的表达和调控。
