Inducible Lung Epithelial Resistance Requires Multisource Reactive Oxygen Species Generation To Protect against Viral Infections

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dc.citation.journalTitlemBioen_US
dc.contributor.authorKirkpatrick, Carson T.en_US
dc.contributor.authorWang, Yongxingen_US
dc.contributor.authorJuarez, Miguel M. Leivaen_US
dc.contributor.authorShivshankar, Poojaen_US
dc.contributor.authorGarcía, Jezreel Pantaleónen_US
dc.contributor.authorPlumer, Alexandria K.en_US
dc.contributor.authorKulkarni, Vikram V.en_US
dc.contributor.authorWare, Hayden H.en_US
dc.contributor.authorGulraiz, Fahaden_US
dc.contributor.authorCavasos, Miguel A. Chavezen_US
dc.contributor.authorZayes, Gabriela Martinezen_US
dc.contributor.authorWali, Shradhaen_US
dc.contributor.authorRice, Andrew P.en_US
dc.contributor.authorLiu, Hongbingen_US
dc.contributor.authorTour, James M.en_US
dc.contributor.authorSikkema, William K.A.en_US
dc.contributor.authorSolbes, Ana S. Cruzen_US
dc.contributor.authorYouker, Keith A.en_US
dc.contributor.authorTuvim, Michael J.en_US
dc.contributor.authorDickey, Burton F.en_US
dc.contributor.authorEvans, Scott E.en_US
dc.date.accessioned2019-01-24T16:07:59Zen_US
dc.date.available2019-01-24T16:07:59Zen_US
dc.date.issued2018en_US
dc.description.abstractViral pneumonias cause profound worldwide morbidity, necessitating novel strategies to prevent and treat these potentially lethal infections. Stimulation of intrinsic lung defenses via inhalation of synergistically acting Toll-like receptor (TLR) agonists protects mice broadly against pneumonia, including otherwise-lethal viral infections, providing a potential opportunity to mitigate infectious threats. As intact lung epithelial TLR signaling is required for the inducible resistance and as these cells are the principal targets of many respiratory viruses, the capacity of lung epithelial cells to be therapeutically manipulated to function as autonomous antiviral effectors was investigated. Our work revealed that mouse and human lung epithelial cells could be stimulated to generate robust antiviral responses that both reduce viral burden and enhance survival of isolated cells and intact animals. The antiviral protection required concurrent induction of epithelial reactive oxygen species (ROS) from both mitochondrial and dual oxidase sources, although neither type I interferon enrichment nor type I interferon signaling was required for the inducible protection. Taken together, these findings establish the sufficiency of lung epithelial cells to generate therapeutically inducible antiviral responses, reveal novel antiviral roles for ROS, provide mechanistic insights into inducible resistance, and may provide an opportunity to protect patients from viral pneumonia during periods of peak vulnerability.IMPORTANCE Viruses are the most commonly identified causes of pneumonia and inflict unacceptable morbidity, despite currently available therapies. While lung epithelial cells are principal targets of respiratory viruses, they have also been recently shown to contribute importantly to therapeutically inducible antimicrobial responses. This work finds that lung cells can be stimulated to protect themselves against viral challenges, even in the absence of leukocytes, both reducing viral burden and improving survival. Further, it was found that the protection occurs via unexpected induction of reactive oxygen species (ROS) from spatially segregated sources without reliance on type I interferon signaling. Coordinated multisource ROS generation has not previously been described against viruses, nor has ROS generation been reported for epithelial cells against any pathogen. Thus, these findings extend the potential clinical applications for the strategy of inducible resistance to protect vulnerable people against viral infections and also provide new insights into the capacity of lung cells to protect against infections via novel ROS-dependent mechanisms.en_US
dc.identifier.citationKirkpatrick, Carson T., Wang, Yongxing, Juarez, Miguel M. Leiva, et al.. "Inducible Lung Epithelial Resistance Requires Multisource Reactive Oxygen Species Generation To Protect against Viral Infections." <i>mBio,</i> (2018) American Society for Microbiology: https://doi.org/10.1128/mBio.00696-18.en_US
dc.identifier.digitale00696-18.fullen_US
dc.identifier.doihttps://doi.org/10.1128/mBio.00696-18en_US
dc.identifier.urihttps://hdl.handle.net/1911/105124en_US
dc.language.isoengen_US
dc.publisherAmerican Society for Microbiologyen_US
dc.rightsThis is an open-access article distributed under the terms of the Creative Commons Attribution 4.0 International license.en_US
dc.rights.urihttps://creativecommons.org/licenses/by/4.0/en_US
dc.subject.keywordToll-like receptorsen_US
dc.subject.keywordinducible resistanceen_US
dc.subject.keywordlung epitheliumen_US
dc.subject.keywordmucosal immunityen_US
dc.subject.keywordreactive oxygen speciesen_US
dc.subject.keywordviral pneumoniaen_US
dc.titleInducible Lung Epithelial Resistance Requires Multisource Reactive Oxygen Species Generation To Protect against Viral Infectionsen_US
dc.typeJournal articleen_US
dc.type.dcmiTexten_US
dc.type.publicationpublisher versionen_US
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