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The methyltransferase Setdb2 mediates virus-induced susceptibility to bacterial superinfection.

  • Schliehe C CeMM Research Center for Molecular Medicine of the Austrian Academy of Sciences, Vienna, Austria.
  • Flynn EK Center for Cancer Research, National Cancer Institute, Frederick, MD, USA.
  • Vilagos B CeMM Research Center for Molecular Medicine of the Austrian Academy of Sciences, Vienna, Austria.
  • Richson U CeMM Research Center for Molecular Medicine of the Austrian Academy of Sciences, Vienna, Austria.
  • Swaminanthan S Seattle Biomedical Research Institute, Seattle, WA, USA.
  • Bosnjak B Department of Dermatology, DIAID, Experimental Allergy, Medical University of Vienna, Vienna, Austria.
  • Bauer L CeMM Research Center for Molecular Medicine of the Austrian Academy of Sciences, Vienna, Austria.
  • Kandasamy RK CeMM Research Center for Molecular Medicine of the Austrian Academy of Sciences, Vienna, Austria.
  • Griesshammer IM CeMM Research Center for Molecular Medicine of the Austrian Academy of Sciences, Vienna, Austria.
  • Kosack L CeMM Research Center for Molecular Medicine of the Austrian Academy of Sciences, Vienna, Austria.
  • Schmitz F Seattle Biomedical Research Institute, Seattle, WA, USA.
  • Litvak V University of Massachusetts, Worcester, MA, USA.
  • Sissons J Seattle Biomedical Research Institute, Seattle, WA, USA.
  • Lercher A CeMM Research Center for Molecular Medicine of the Austrian Academy of Sciences, Vienna, Austria.
  • Bhattacharya A CeMM Research Center for Molecular Medicine of the Austrian Academy of Sciences, Vienna, Austria.
  • Khamina K CeMM Research Center for Molecular Medicine of the Austrian Academy of Sciences, Vienna, Austria.
  • Trivett AL Center for Cancer Research, National Cancer Institute, Frederick, MD, USA.
  • Tessarollo L Center for Cancer Research, National Cancer Institute, Frederick, MD, USA.
  • Mesteri I Department of Pathology, Medical University of Vienna, Vienna, Austria.
  • Hladik A CeMM Research Center for Molecular Medicine of the Austrian Academy of Sciences, Vienna, Austria.
  • Merkler D Department of Pathology and Immunology, Division of Clinical Pathology, University & University Hospital of Geneva, Geneva, Switzerland.
  • Kubicek S CeMM Research Center for Molecular Medicine of the Austrian Academy of Sciences, Vienna, Austria.
  • Knapp S CeMM Research Center for Molecular Medicine of the Austrian Academy of Sciences, Vienna, Austria.
  • Epstein MM Department of Dermatology, DIAID, Experimental Allergy, Medical University of Vienna, Vienna, Austria.
  • Symer DE Center for Cancer Research, National Cancer Institute, Frederick, MD, USA.
  • Aderem A Seattle Biomedical Research Institute, Seattle, WA, USA.
  • Bergthaler A CeMM Research Center for Molecular Medicine of the Austrian Academy of Sciences, Vienna, Austria.
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  • 2014-11-25
Published in:
  • Nature immunology. - 2015
Animals
Chemokine CXCL1
Disease Susceptibility
Female
Histone-Lysine N-Methyltransferase
Interferon Type I
Male
Mice, Inbred C57BL
Mice, Knockout
NF-kappa B
Oligonucleotide Array Sequence Analysis
Orthomyxoviridae
Orthomyxoviridae Infections
Pneumonia
RNA
Real-Time Polymerase Chain Reaction
Specific Pathogen-Free Organisms
Superinfection
English 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.
Language
  • English
Open access status
green
Identifiers
Persistent URL
https://sonar.ch/global/documents/46540
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