The methyltransferase Setdb2 mediates virus-induced susceptibility to bacterial superinfection

Christopher Schliehe; Elizabeth K. Flynn; Bojan Vilagos; Udochuku Richson; Savitha Swaminathan; Berislav Bosnjak; Lisa Bauer; Richard K. Kandasamy; Isabel M. Griesshammer; Lindsay Kosack; Frank Schmitz; Vladimir Litvak; James Sissons; Alexander Lercher; Anannya Bhattacharya; Kseniya Khamina; Anna L. Trivett; Lino Tessarollo; Ildiko Mesteri; Anastasiya Hladik; Doron Merkler; Stefan Kubicek; Sylvia Knapp; Michelle M. Epstein; David E. Symer; Alan Aderem; Andreas Bergthaler

doi:10.1038/ni.3046

The methyltransferase Setdb2 mediates virus-induced susceptibility to bacterial superinfection

Christopher Schliehe, Elizabeth K. Flynn, Bojan Vilagos, Udochuku Richson, Savitha Swaminathan, Berislav Bosnjak, Lisa Bauer, Richard K. Kandasamy, Isabel M. Griesshammer, Lindsay Kosack, Frank Schmitz, Vladimir Litvak, James Sissons, Alexander Lercher, Anannya Bhattacharya, Kseniya Khamina, Anna L. Trivett, Lino Tessarollo, Ildiko Mesteri, Anastasiya HladikDoron Merkler, Stefan Kubicek, Sylvia Knapp, Michelle M. Epstein, David E. Symer, Alan Aderem, Andreas Bergthaler^*

^*Corresponding author for this work

Research output: Contribution to journal › Article › Academic › peer-review

111 Citations (Scopus)

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-Î° B. 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-κ B pathways represents an important mechanism for virus-induced susceptibility to bacterial superinfection.

Original language	English
Pages (from-to)	67-74
Number of pages	8
Journal	Nature Immunology
Volume	16
Issue number	1
DOIs	https://doi.org/10.1038/ni.3046
Publication status	Published - Jan 2015
Externally published	Yes

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© 2015 Nature America, Inc.

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Schliehe, C., Flynn, E. K., Vilagos, B., Richson, U., Swaminathan, S., Bosnjak, B., Bauer, L., Kandasamy, R. K., Griesshammer, I. M., Kosack, L., Schmitz, F., Litvak, V., Sissons, J., Lercher, A., Bhattacharya, A., Khamina, K., Trivett, A. L., Tessarollo, L., Mesteri, I., ... Bergthaler, A. (2015). The methyltransferase Setdb2 mediates virus-induced susceptibility to bacterial superinfection. Nature Immunology, 16(1), 67-74. https://doi.org/10.1038/ni.3046

@article{0547730fe4bc433bbe45025210174810,

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-{\^I}° B. 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-κ B pathways represents an important mechanism for virus-induced susceptibility to bacterial superinfection.",

author = "Christopher Schliehe and Flynn, {Elizabeth K.} and Bojan Vilagos and Udochuku Richson and Savitha Swaminathan and Berislav Bosnjak and Lisa Bauer and Kandasamy, {Richard K.} and Griesshammer, {Isabel M.} and Lindsay Kosack and Frank Schmitz and Vladimir Litvak and James Sissons and Alexander Lercher and Anannya Bhattacharya and Kseniya Khamina and Trivett, {Anna L.} and Lino Tessarollo and Ildiko Mesteri and Anastasiya Hladik and Doron Merkler and Stefan Kubicek and Sylvia Knapp and Epstein, {Michelle M.} and Symer, {David E.} and Alan Aderem and Andreas Bergthaler",

note = "Publisher Copyright: {\textcopyright} 2015 Nature America, Inc.",

year = "2015",

month = jan,

doi = "10.1038/ni.3046",

language = "English",

volume = "16",

pages = "67--74",

journal = "Nature Immunology",

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Schliehe, C, Flynn, EK, Vilagos, B, Richson, U, Swaminathan, S, Bosnjak, B, Bauer, L, Kandasamy, RK, Griesshammer, IM, Kosack, L, Schmitz, F, Litvak, V, Sissons, J, Lercher, A, Bhattacharya, A, Khamina, K, Trivett, AL, Tessarollo, L, Mesteri, I, Hladik, A, Merkler, D, Kubicek, S, Knapp, S, Epstein, MM, Symer, DE, Aderem, A & Bergthaler, A 2015, 'The methyltransferase Setdb2 mediates virus-induced susceptibility to bacterial superinfection', Nature Immunology, vol. 16, no. 1, pp. 67-74. https://doi.org/10.1038/ni.3046

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AU - Schliehe, Christopher

AU - Flynn, Elizabeth K.

AU - Vilagos, Bojan

AU - Richson, Udochuku

AU - Swaminathan, Savitha

AU - Bosnjak, Berislav

AU - Bauer, Lisa

AU - Kandasamy, Richard K.

AU - Griesshammer, Isabel M.

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AU - Schmitz, Frank

AU - Litvak, Vladimir

AU - Sissons, James

AU - Lercher, Alexander

AU - Bhattacharya, Anannya

AU - Khamina, Kseniya

AU - Trivett, Anna L.

AU - Tessarollo, Lino

AU - Mesteri, Ildiko

AU - Hladik, Anastasiya

AU - Merkler, Doron

AU - Kubicek, Stefan

AU - Knapp, Sylvia

AU - Epstein, Michelle M.

AU - Symer, David E.

AU - Aderem, Alan

AU - Bergthaler, Andreas

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N2 - 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-Î° B. 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-κ B pathways represents an important mechanism for virus-induced susceptibility to bacterial superinfection.

AB - 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-Î° B. 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-κ B pathways represents an important mechanism for virus-induced susceptibility to bacterial superinfection.

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SP - 67

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JO - Nature Immunology

JF - Nature Immunology

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The methyltransferase Setdb2 mediates virus-induced susceptibility to bacterial superinfection

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