Dataset Information

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-?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-?B pathways represents an important mechanism for virus-induced susceptibility to bacterial superinfection.

SUBMITTER: Schliehe C

PROVIDER: S-EPMC4320687 | biostudies-literature | 2015 Jan

REPOSITORIES: biostudies-literature

ACCESS DATA

Publications

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

Schliehe Christopher C Flynn Elizabeth K EK Vilagos Bojan B Richson Udochuku U Swaminanthan Savitha S Bosnjak Berislav B Bauer Lisa L Kandasamy Richard K RK Griesshammer Isabel M IM Kosack Lindsay L Schmitz Frank F Litvak Vladimir V Sissons James J Lercher Alexander A Bhattacharya Anannya A Khamina Kseniya K Trivett Anna L AL Tessarollo Lino L Mesteri Ildiko I Hladik Anastasiya A Merkler Doron D Kubicek Stefan S Knapp Sylvia S Epstein Michelle M MM Symer David E DE Aderem Alan A Bergthaler Andreas A

Nature immunology 20141124 1

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 pr ...[more]

PMID: 25419628

Similar Datasets

Project description:Bacterial superinfections are a primary cause of death during influenza pandemics and epidemics. Type I interferon (IFN) signaling contributes to increased susceptibility of mice to bacterial superinfection around day 7 post-influenza A virus (IAV) infection. Here we demonstrate that the reduced susceptibility to methicillin-resistant Staphylococcus aureus (MRSA) at day 3 post-IAV infection, which we previously reported was due to interleukin-13 (IL-13)/IFN-? responses, is also dependent on type I IFN signaling and its subsequent requirement for protective IL-13 production. We found, through utilization of blocking antibodies, that reduced susceptibility to MRSA at day 3 post-IAV infection was IFN-? dependent, whereas the increased susceptibility at day 7 was IFN-? dependent. IFN-? signaling early in IAV infection was required for MRSA clearance, whereas IFN-? signaling late in infection was not, though it did mediate increased susceptibility to MRSA at that time. Type I IFN receptor (IFNAR) signaling in CD11c(+) and Ly6G(+) cells was required for the observed reduced susceptibility at day 3 post-IAV infection. Depletion of Ly6G(+) cells in mice in which IFNAR signaling was either blocked or deleted indicated that Ly6G(+) cells were responsible for the IFNAR signaling-dependent susceptibility to MRSA superinfection at day 7 post-IAV infection. Thus, during IAV infection, the temporal differences in type I IFN signaling increased bactericidal activity of both CD11c(+) and Ly6G(+) cells at day 3 and reduced effector function of Ly6G(+) cells at day 7. The temporal differential outcomes induced by IFN-? (day 3) and IFN-? (day 7) signaling through the same IFNAR resulted in differential susceptibility to MRSA at 3 and 7 days post-IAV infection.Approximately 114,000 hospitalizations and 40,000 annual deaths in the United States are associated with influenza A virus (IAV) infections. Frequently, these deaths are due to community-acquired Gram-positive bacterial species, many of which show increasing resistance to antibiotic therapy. Severe complications, including parapneumonic empyema and necrotizing pneumonia, can arise, depending on virulence factors expressed by either the virus or bacteria. Unfortunately, we are unable to control the expression of these virulence factors, making host responses a logical target for therapeutic interventions. Moreover, interactions between virus, host, and bacteria that exacerbate IAV-related morbidities and mortalities are largely unknown. Here, we show that type I interferon (IFN) expression can modulate susceptibility to methicillin-resistant Staphylococcus aureus (MRSA) infection, with IFN-? reducing host susceptibility to MRSA infection while IFN-? increases susceptibility. Our data indicate that treatments designed to augment IFN-? and/or inhibit IFN-? production around day 7 post-IAV infection could reduce susceptibility to deadly superinfections.

Dataset Information

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

Publications

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

Similar Datasets

OmicsDI is part of the ELIXIR infrastructure

Tweets