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

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dc.citation.journalTitlemBio
dc.contributor.authorKirkpatrick, Carson T.
dc.contributor.authorWang, Yongxing
dc.contributor.authorJuarez, Miguel M. Leiva
dc.contributor.authorShivshankar, Pooja
dc.contributor.authorGarcía, Jezreel Pantaleón
dc.contributor.authorPlumer, Alexandria K.
dc.contributor.authorKulkarni, Vikram V.
dc.contributor.authorWare, Hayden H.
dc.contributor.authorGulraiz, Fahad
dc.contributor.authorCavasos, Miguel A. Chavez
dc.contributor.authorZayes, Gabriela Martinez
dc.contributor.authorWali, Shradha
dc.contributor.authorRice, Andrew P.
dc.contributor.authorLiu, Hongbing
dc.contributor.authorTour, James M.
dc.contributor.authorSikkema, William K.A.
dc.contributor.authorSolbes, Ana S. Cruz
dc.contributor.authorYouker, Keith A.
dc.contributor.authorTuvim, Michael J.
dc.contributor.authorDickey, Burton F.
dc.contributor.authorEvans, Scott E.
dc.date.accessioned2019-01-24T16:07:59Z
dc.date.available2019-01-24T16:07:59Z
dc.date.issued2018
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.
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.
dc.identifier.digitale00696-18.full
dc.identifier.doihttps://doi.org/10.1128/mBio.00696-18
dc.identifier.urihttps://hdl.handle.net/1911/105124
dc.language.isoeng
dc.publisherAmerican Society for Microbiology
dc.rightsThis is an open-access article distributed under the terms of the Creative Commons Attribution 4.0 International license.
dc.rights.urihttps://creativecommons.org/licenses/by/4.0/
dc.subject.keywordToll-like receptors
dc.subject.keywordinducible resistance
dc.subject.keywordlung epithelium
dc.subject.keywordmucosal immunity
dc.subject.keywordreactive oxygen species
dc.subject.keywordviral pneumonia
dc.titleInducible Lung Epithelial Resistance Requires Multisource Reactive Oxygen Species Generation To Protect against Viral Infections
dc.typeJournal article
dc.type.dcmiText
dc.type.publicationpublisher version
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