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Published on: August 17, 2018
Ifitm3 limits the severity of acute influenza in mice
Charles C Bailey1, I-Chueh Huang, Christina Kam
1Department of Microbiology and Immunobiology, Harvard Medical School, New England Primate Research Center, Southborough, Massachusetts, United States of America. charles_bailey@hms.harvard.edu
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.
Insights
Interferon-induced transmembrane protein 3 (IFITM3) is crucial for limiting influenza A virus infection in mice. Its absence accelerates disease, increases mortality, and elevates viral loads, highlighting its vital role in host defense.
Area of Science:
- Virology
- Immunology
- Molecular Biology
Background:
- Interferon-induced transmembrane (IFITM) proteins restrict viral entry in vitro.
- Influenza A virus (IAV) poses a significant global health threat.
Purpose of the Study:
- To investigate the in vivo role of IFITM proteins, particularly IFITM3, in influenza A virus infection.
- To elucidate the expression and regulation of IFITM3 during viral infection.
Main Methods:
- Utilized knockout mouse models lacking the Ifitm locus or specifically Ifitm3.
- Assessed disease progression, mortality, and viral burdens post-IAV infection.
- Examined Ifitm3 expression in respiratory tissues and its regulation by interferons and cytokines.
Main Results:
- Mice lacking the Ifitm locus or Ifitm3 showed accelerated IAV disease, higher mortality, and increased viral loads.
- Ifitm3 is expressed in key IAV target cells (alveolar type II pneumocytes, respiratory epithelial cells).
- Ifitm3 expression is induced by type I/II interferons and gp130 cytokines (IL-6, oncostatin M).
Conclusions:
- IFITM3 plays a central role in limiting acute influenza A virus infection in vivo.
- Multiple cytokine signals contribute to cell/tissue-specific Ifitm3 expression.
- Understanding IFITM3 regulation offers insights into host antiviral defense mechanisms.
