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dc.contributor.authorKirkpatrick, Carson T.
Wang, Yongxing
Juarez, Miguel M. Leiva
Shivshankar, Pooja
García, Jezreel Pantaleón
Plumer, Alexandria K.
Kulkarni, Vikram V.
Ware, Hayden H.
Gulraiz, Fahad
Cavasos, Miguel A. Chavez
Zayes, Gabriela Martinez
Wali, Shradha
Rice, Andrew P.
Liu, Hongbing
Tour, James M.
Sikkema, William K.A.
Solbes, Ana S. Cruz
Youker, Keith A.
Tuvim, Michael J.
Dickey, Burton F.
Evans, Scott E.
dc.date.accessioned 2019-01-24T16:07:59Z
dc.date.available 2019-01-24T16:07:59Z
dc.date.issued 2018
dc.identifier.citation Kirkpatrick, 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." mBio, (2018) American Society for Microbiology: https://doi.org/10.1128/mBio.00696-18.
dc.identifier.urihttps://hdl.handle.net/1911/105124
dc.description.abstract Viral 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.language.iso eng
dc.publisher American Society for Microbiology
dc.rights This 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.title Inducible Lung Epithelial Resistance Requires Multisource Reactive Oxygen Species Generation To Protect against Viral Infections
dc.type Journal article
dc.citation.journalTitle mBio
dc.subject.keywordToll-like receptors
inducible resistance
lung epithelium
mucosal immunity
reactive oxygen species
viral pneumonia
dc.identifier.digital e00696-18.full
dc.type.dcmi Text
dc.identifier.doihttps://doi.org/10.1128/mBio.00696-18
dc.identifier.pmcid PMC5954225
dc.identifier.pmid 29764948
dc.type.publication publisher version


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This is an open-access article distributed under the terms of the Creative Commons Attribution 4.0 International license.
Except where otherwise noted, this item's license is described as This is an open-access article distributed under the terms of the Creative Commons Attribution 4.0 International license.