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dc.contributor.authorShirey, K.A.
dc.contributor.authorPerkins, D.J.
dc.contributor.authorLai, W.
dc.date.accessioned2019-09-13T16:41:57Z
dc.date.available2019-09-13T16:41:57Z
dc.date.issued2019
dc.identifier.urihttps://www.scopus.com/inward/record.uri?eid=2-s2.0-85065758703&doi=10.1128%2fmBio.00810-19&partnerID=40&md5=daf79e9f03e6562f1d3eff837d8bc317
dc.identifier.urihttp://hdl.handle.net/10713/10668
dc.description.abstractWe previously reported that the Toll-like receptor 4 (TLR4) antagonist Eritoran blocks acute lung injury (ALI) therapeutically in mouse and cotton rat models of influenza. However, secondary (2°) bacterial infection following influenza virus infection is associated with excess morbidity and mortality. Wild-type (WT) mice infected with mouse-adapted influenza A/Puerto Rico/8/34 virus (PR8) and, 7 days later, with Streptococcus pneumoniae serotype 3 (Sp3) exhibited significantly enhanced lung pathology and lethality that was reversed by Eritoran therapy after PR8 infection but before Sp3 infection. Cotton rats infected with nonadapted pH1N1 influenza virus and then superinfected with methicillin-resistant Staphylococcus aureus also exhibited increased lung pathology and serum high-mobility-group box 1 (HMGB1) levels, both of which were blunted by Eritoran therapy. In mice, PR8 infection suppressed Sp3-induced CXCL1 and CXCL2 mRNA, reducing neutrophil infiltration and increasing the bacterial burden, all of which were reversed by Eritoran treatment. While beta interferon (IFN-β)-deficient (IFN-β−/−) mice are highly susceptible to PR8, they exhibited delayed death upon Sp3 superinfection, indicating that while IFN-β was protective against influenza, it negatively impacted the host response to Sp3. IFN-β-treated WT macrophages selectively suppressed Sp3-induced CXCL1/CXCL2 transcriptionally, as evidenced by reduced recruitment of RNA polymerase II to the CXCL1 promoter. Thus, influenza establishes a “trained” state of immunosuppression toward 2° bacterial infection, in part through the potent induction of IFN-β and its downstream transcriptional regulation of chemokines, an effect reversed by Eritoran. IMPORTANCE: Enhanced susceptibility to 2° bacterial infections following infection with influenza virus is a global health concern that accounts for many hospitalizations and deaths, particularly during pandemics. The complexity of the impaired host immune response during 2° bacterial infection has been widely studied. Both type I IFN and neutrophil dysfunction through decreased chemokine production have been implicated as mechanisms underlying enhanced susceptibility to 2° bacterial infections. Our findings support the conclusion that selective suppression of CXCL1/CXCL2 represents an IFN-β-mediated “training” of the macrophage transcriptional response to TLR2 agonists and that blocking of TLR4 therapeutically with Eritoran after influenza virus infection reverses this suppression by blunting influenza-induced IFN-β. Copyright 2019 Shirey et al.en_US
dc.description.sponsorshipThis work is supported by NIH grants AI104541, AI125215 (to S.N.V. and J.C.G.B.), and AI123371 (to S.N.V.).en_US
dc.description.urihttps://doi.org/10.1128/mBio.00810-19en_US
dc.language.isoen-USen_US
dc.publisherAmerican Society for Microbiologyen_US
dc.relation.ispartofmBio
dc.subjectCotton ratsen_US
dc.subjectIFN-βen_US
dc.subjectInfluenzaen_US
dc.subjectMacrophage trainingen_US
dc.subjectMRSAen_US
dc.subjectSecondary bacterial infectionen_US
dc.subjectStreptococcus pneumoniaeen_US
dc.subjectTLR4en_US
dc.titleInfluenza "Trains" the host for enhanced susceptibility to secondary bacterial infectionen_US
dc.typeArticleen_US
dc.identifier.doi10.1128/mBio.00810-19
dc.identifier.pmid31064834


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