Influenza “Trains” the Host for Enhanced Susceptibility to Secondary Bacterial Infection

ABSTRACT We 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...

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Autores principales:	Kari Ann Shirey, Darren J. Perkins, Wendy Lai, Wei Zhang, Lurds R. Fernando, Fabian Gusovsky, Jorge C. G. Blanco, Stefanie N. Vogel
Formato:	article
Lenguaje:	EN
Publicado:	American Society for Microbiology 2019
Materias:	IFN-β MRSA Streptococcus pneumoniae TLR4 cotton rats influenza Microbiology QR1-502
Acceso en línea:	https://doaj.org/article/d53eb0ce4dd8466f9c6dd00fde7aaa19
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spelling	oai:doaj.org-article:d53eb0ce4dd8466f9c6dd00fde7aaa192021-11-15T15:55:25ZInfluenza “Trains” the Host for Enhanced Susceptibility to Secondary Bacterial Infection10.1128/mBio.00810-192150-7511https://doaj.org/article/d53eb0ce4dd8466f9c6dd00fde7aaa192019-06-01T00:00:00Zhttps://journals.asm.org/doi/10.1128/mBio.00810-19https://doaj.org/toc/2150-7511ABSTRACT We 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.Kari Ann ShireyDarren J. PerkinsWendy LaiWei ZhangLurds R. FernandoFabian GusovskyJorge C. G. BlancoStefanie N. VogelAmerican Society for MicrobiologyarticleIFN-βMRSAStreptococcus pneumoniaeTLR4cotton ratsinfluenzaMicrobiologyQR1-502ENmBio, Vol 10, Iss 3 (2019)
institution	DOAJ
collection	DOAJ
language	EN
topic	IFN-β MRSA Streptococcus pneumoniae TLR4 cotton rats influenza Microbiology QR1-502
spellingShingle	IFN-β MRSA Streptococcus pneumoniae TLR4 cotton rats influenza Microbiology QR1-502 Kari Ann Shirey Darren J. Perkins Wendy Lai Wei Zhang Lurds R. Fernando Fabian Gusovsky Jorge C. G. Blanco Stefanie N. Vogel Influenza “Trains” the Host for Enhanced Susceptibility to Secondary Bacterial Infection
description	ABSTRACT We 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.
format	article
author	Kari Ann Shirey Darren J. Perkins Wendy Lai Wei Zhang Lurds R. Fernando Fabian Gusovsky Jorge C. G. Blanco Stefanie N. Vogel
author_facet	Kari Ann Shirey Darren J. Perkins Wendy Lai Wei Zhang Lurds R. Fernando Fabian Gusovsky Jorge C. G. Blanco Stefanie N. Vogel
author_sort	Kari Ann Shirey
title	Influenza “Trains” the Host for Enhanced Susceptibility to Secondary Bacterial Infection
title_short	Influenza “Trains” the Host for Enhanced Susceptibility to Secondary Bacterial Infection
title_full	Influenza “Trains” the Host for Enhanced Susceptibility to Secondary Bacterial Infection
title_fullStr	Influenza “Trains” the Host for Enhanced Susceptibility to Secondary Bacterial Infection
title_full_unstemmed	Influenza “Trains” the Host for Enhanced Susceptibility to Secondary Bacterial Infection
title_sort	influenza “trains” the host for enhanced susceptibility to secondary bacterial infection
publisher	American Society for Microbiology
publishDate	2019
url	https://doaj.org/article/d53eb0ce4dd8466f9c6dd00fde7aaa19
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Influenza “Trains” the Host for Enhanced Susceptibility to Secondary Bacterial Infection

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