The methyltransferase Setdb2 mediates virus-induced susceptibility to bacterial superinfection

Nat Immunol. 2015 Jan;16(1):67-74. doi: 10.1038/ni.3046. Epub 2014 Nov 24.


Immune responses are tightly regulated to ensure efficient pathogen clearance while avoiding tissue damage. Here we report that Setdb2 was the only protein lysine methyltransferase induced during infection with influenza virus. Setdb2 expression depended on signaling via type I interferons, and Setdb2 repressed expression of the gene encoding the neutrophil attractant CXCL1 and other genes that are targets of the transcription factor NF-κB. This coincided with occupancy by Setdb2 at the Cxcl1 promoter, which in the absence of Setdb2 displayed diminished trimethylation of histone H3 Lys9 (H3K9me3). Mice with a hypomorphic gene-trap construct of Setdb2 exhibited increased infiltration of neutrophils during sterile lung inflammation and were less sensitive to bacterial superinfection after infection with influenza virus. This suggested that a Setdb2-mediated regulatory crosstalk between the type I interferons and NF-κB pathways represents an important mechanism for virus-induced susceptibility to bacterial superinfection.

Publication types

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

MeSH terms

  • Animals
  • Chemokine CXCL1 / immunology
  • Disease Susceptibility
  • Female
  • Histone-Lysine N-Methyltransferase / immunology*
  • Interferon Type I / immunology
  • Male
  • Mice, Inbred C57BL
  • Mice, Knockout
  • NF-kappa B / immunology*
  • Oligonucleotide Array Sequence Analysis
  • Orthomyxoviridae / immunology*
  • Orthomyxoviridae Infections / enzymology
  • Orthomyxoviridae Infections / immunology*
  • Orthomyxoviridae Infections / virology
  • Pneumonia / enzymology
  • Pneumonia / immunology*
  • Pneumonia / virology
  • RNA / chemistry
  • RNA / genetics
  • Real-Time Polymerase Chain Reaction
  • Specific Pathogen-Free Organisms
  • Superinfection / enzymology
  • Superinfection / immunology*
  • Superinfection / microbiology


  • Chemokine CXCL1
  • Cxcl1 protein, mouse
  • Interferon Type I
  • NF-kappa B
  • RNA
  • Histone-Lysine N-Methyltransferase