Ifitm3 Limits the Severity of Acute Influenza in Mice

PLoS Pathog. 2012 Sep;8(9):e1002909. doi: 10.1371/journal.ppat.1002909. Epub 2012 Sep 6.

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.

Publication types

  • Research Support, N.I.H., Intramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • 3T3 Cells
  • Acute Disease
  • Animals
  • Cells, Cultured
  • Chick Embryo
  • Disease Resistance / genetics
  • Genetic Predisposition to Disease / genetics
  • Humans
  • Influenza A virus / pathogenicity*
  • Membrane Proteins / genetics
  • Membrane Proteins / metabolism
  • Membrane Proteins / physiology*
  • Mice
  • Mice, Inbred C57BL
  • Mice, Knockout
  • NIH 3T3 Cells
  • Orthomyxoviridae Infections / genetics*
  • Orthomyxoviridae Infections / pathology
  • Orthomyxoviridae Infections / prevention & control
  • Severity of Illness Index

Substances

  • Membrane Proteins
  • fragilis protein, mouse