title: The methyltransferase Setdb2 mediates virus-induced susceptibility to bacterial superinfection.
abstract: 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.
authors.affiliation: CeMM Research Center for Molecular Medicine of the Austrian Academy of Sciences, Vienna, Austria.
authors.forename: Christopher
authors.initials: C
authors.lastname: Schliehe
authors.affiliation: Center for Cancer Research, National Cancer Institute, Frederick, MD, USA.
authors.forename: Elizabeth K
authors.initials: EK
authors.lastname: Flynn
authors.affiliation: CeMM Research Center for Molecular Medicine of the Austrian Academy of Sciences, Vienna, Austria.
authors.forename: Bojan
authors.initials: B
authors.lastname: Vilagos
authors.affiliation: CeMM Research Center for Molecular Medicine of the Austrian Academy of Sciences, Vienna, Austria.
authors.forename: Udochuku
authors.initials: U
authors.lastname: Richson
authors.affiliation: Seattle Biomedical Research Institute, Seattle, WA, USA.
authors.forename: Savitha
authors.initials: S
authors.lastname: Swaminanthan
authors.affiliation: Department of Dermatology, DIAID, Experimental Allergy, Medical University of Vienna, Vienna, Austria.
authors.forename: Berislav
authors.initials: B
authors.lastname: Bosnjak
authors.affiliation: CeMM Research Center for Molecular Medicine of the Austrian Academy of Sciences, Vienna, Austria.
authors.forename: Lisa
authors.initials: L
authors.lastname: Bauer
authors.affiliation: CeMM Research Center for Molecular Medicine of the Austrian Academy of Sciences, Vienna, Austria.
authors.forename: Richard K
authors.initials: RK
authors.lastname: Kandasamy
authors.affiliation: CeMM Research Center for Molecular Medicine of the Austrian Academy of Sciences, Vienna, Austria.
authors.forename: Isabel M
authors.initials: IM
authors.lastname: Griesshammer
authors.affiliation: CeMM Research Center for Molecular Medicine of the Austrian Academy of Sciences, Vienna, Austria.
authors.forename: Lindsay
authors.initials: L
authors.lastname: Kosack
authors.affiliation: Seattle Biomedical Research Institute, Seattle, WA, USA.
authors.forename: Frank
authors.initials: F
authors.lastname: Schmitz
authors.affiliation: University of Massachusetts, Worcester, MA, USA.
authors.forename: Vladimir
authors.initials: V
authors.lastname: Litvak
authors.affiliation: Seattle Biomedical Research Institute, Seattle, WA, USA.
authors.forename: James
authors.initials: J
authors.lastname: Sissons
authors.affiliation: CeMM Research Center for Molecular Medicine of the Austrian Academy of Sciences, Vienna, Austria.
authors.forename: Alexander
authors.initials: A
authors.lastname: Lercher
authors.affiliation: CeMM Research Center for Molecular Medicine of the Austrian Academy of Sciences, Vienna, Austria.
authors.forename: Anannya
authors.initials: A
authors.lastname: Bhattacharya
authors.affiliation: CeMM Research Center for Molecular Medicine of the Austrian Academy of Sciences, Vienna, Austria.
authors.forename: Kseniya
authors.initials: K
authors.lastname: Khamina
authors.affiliation: Center for Cancer Research, National Cancer Institute, Frederick, MD, USA.
authors.forename: Anna L
authors.initials: AL
authors.lastname: Trivett
authors.affiliation: Center for Cancer Research, National Cancer Institute, Frederick, MD, USA.
authors.forename: Lino
authors.initials: L
authors.lastname: Tessarollo
authors.affiliation: Department of Pathology, Medical University of Vienna, Vienna, Austria.
authors.forename: Ildiko
authors.initials: I
authors.lastname: Mesteri
authors.affiliation: CeMM Research Center for Molecular Medicine of the Austrian Academy of Sciences, Vienna, Austria.|Department of Medicine 1, Medical University of Vienna, Vienna, Austria.
authors.forename: Anastasiya
authors.initials: A
authors.lastname: Hladik
authors.affiliation: Department of Pathology and Immunology, Division of Clinical Pathology, University & University Hospital of Geneva, Geneva, Switzerland.|Department of Neuropathology, Georg-August-University Goettingen, Germany.
authors.forename: Doron
authors.initials: D
authors.lastname: Merkler
authors.affiliation: CeMM Research Center for Molecular Medicine of the Austrian Academy of Sciences, Vienna, Austria.
authors.forename: Stefan
authors.initials: S
authors.lastname: Kubicek
authors.affiliation: CeMM Research Center for Molecular Medicine of the Austrian Academy of Sciences, Vienna, Austria.|Department of Medicine 1, Medical University of Vienna, Vienna, Austria.
authors.forename: Sylvia
authors.initials: S
authors.lastname: Knapp
authors.affiliation: Department of Dermatology, DIAID, Experimental Allergy, Medical University of Vienna, Vienna, Austria.
authors.forename: Michelle M
authors.initials: MM
authors.lastname: Epstein
authors.affiliation: Center for Cancer Research, National Cancer Institute, Frederick, MD, USA.|Ohio State University Comprehensive Cancer Center, Columbus, OH, USA.
authors.forename: David E
authors.initials: DE
authors.lastname: Symer
authors.affiliation: Seattle Biomedical Research Institute, Seattle, WA, USA.
authors.forename: Alan
authors.initials: A
authors.lastname: Aderem
authors.affiliation: CeMM Research Center for Molecular Medicine of the Austrian Academy of Sciences, Vienna, Austria.
authors.forename: Andreas
authors.initials: A
authors.lastname: Bergthaler
mesh_terms: D000818:Animals; D054360:Chemokine CXCL1 / Q000276:immunology; D004198:Disease Susceptibility; D005260:Female; D011495:Histone-Lysine N-Methyltransferase / Q000276:immunology*; D007370:Interferon Type I / Q000276:immunology; D008297:Male; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D016328:NF-kappa B / Q000276:immunology*; D020411:Oligonucleotide Array Sequence Analysis; D009975:Orthomyxoviridae / Q000276:immunology*; D009976:Orthomyxoviridae Infections / Q000201:enzymology / Q000276:immunology* / Q000821:virology; D011014:Pneumonia / Q000201:enzymology / Q000276:immunology* / Q000821:virology; D012313:RNA / Q000737:chemistry / Q000235:genetics; D060888:Real-Time Polymerase Chain Reaction; D013047:Specific Pathogen-Free Organisms; D015163:Superinfection / Q000201:enzymology / Q000276:immunology* / Q000382:microbiology
chemical_list: D054360:Chemokine CXCL1; C475895:Cxcl1 protein, mouse; D007370:Interferon Type I; D016328:NF-kappa B; D012313:RNA; D011495:Histone-Lysine N-Methyltransferase