Ifitm3 Limits the Severity of Acute Influenza in Mice

Abstract

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. The human genome contains many genes devoted to combating viral infections. Some of these genes encode a family of proteins called interferon-induced transmembrane (IFITM) proteins which were recently discovered to inhibit infection by influenza A viruses in cell culture experiments. Here we show that genetically engineered mice lacking the murine equivalents of the human IFITM genes are more susceptible to influenza than mice with a full complement of these genes. In addition, deletion of one of these genes alone, Ifitm3, made mice equally susceptible to infection, showing that the Ifitm3 protein plays a central role in the control of influenza A virus in living animals. We also show that murine Ifitm proteins are expressed on cells targeted by influenza A viruses and that the control of their expression in animals is more complex than suggested by previous cell culture studies.