Inducible Lung Epithelial Resistance Requires Multisource Reactive Oxygen Species Generation To Protect against Viral Infections
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 pneum...
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American Society for Microbiology
2018
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oai:doaj.org-article:bad5b71e30944f789382fafb101c7a342021-11-15T16:00:26ZInducible Lung Epithelial Resistance Requires Multisource Reactive Oxygen Species Generation To Protect against Viral Infections10.1128/mBio.00696-182150-7511https://doaj.org/article/bad5b71e30944f789382fafb101c7a342018-07-01T00:00:00Zhttps://journals.asm.org/doi/10.1128/mBio.00696-18https://doaj.org/toc/2150-7511ABSTRACT 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.Carson T. KirkpatrickYongxing WangMiguel M. Leiva JuarezPooja ShivshankarJezreel Pantaleón GarcíaAlexandria K. PlumerVikram V. KulkarniHayden H. WareFahad GulraizMiguel A. Chavez CavasosGabriela Martinez ZayasShradha WaliAndrew P. RiceHongbing LiuJames M. TourWilliam K. A. SikkemaAna S. Cruz SolbesKeith A. YoukerMichael J. TuvimBurton F. DickeyScott E. EvansAmerican Society for Microbiologyarticleinducible resistanceToll-like receptorslung epitheliummucosal immunityreactive oxygen speciesviral pneumoniaMicrobiologyQR1-502ENmBio, Vol 9, Iss 3 (2018) |
| institution |
DOAJ |
| collection |
DOAJ |
| language |
EN |
| topic |
inducible resistance Toll-like receptors lung epithelium mucosal immunity reactive oxygen species viral pneumonia Microbiology QR1-502 |
| spellingShingle |
inducible resistance Toll-like receptors lung epithelium mucosal immunity reactive oxygen species viral pneumonia Microbiology QR1-502 Carson T. Kirkpatrick Yongxing Wang Miguel M. Leiva Juarez Pooja Shivshankar Jezreel Pantaleón García Alexandria K. Plumer Vikram V. Kulkarni Hayden H. Ware Fahad Gulraiz Miguel A. Chavez Cavasos Gabriela Martinez Zayas Shradha Wali Andrew P. Rice Hongbing Liu James M. Tour William K. A. Sikkema Ana S. Cruz Solbes Keith A. Youker Michael J. Tuvim Burton F. Dickey Scott E. Evans Inducible Lung Epithelial Resistance Requires Multisource Reactive Oxygen Species Generation To Protect against Viral Infections |
| 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. |
| format |
article |
| author |
Carson T. Kirkpatrick Yongxing Wang Miguel M. Leiva Juarez Pooja Shivshankar Jezreel Pantaleón García Alexandria K. Plumer Vikram V. Kulkarni Hayden H. Ware Fahad Gulraiz Miguel A. Chavez Cavasos Gabriela Martinez Zayas Shradha Wali Andrew P. Rice Hongbing Liu James M. Tour William K. A. Sikkema Ana S. Cruz Solbes Keith A. Youker Michael J. Tuvim Burton F. Dickey Scott E. Evans |
| author_facet |
Carson T. Kirkpatrick Yongxing Wang Miguel M. Leiva Juarez Pooja Shivshankar Jezreel Pantaleón García Alexandria K. Plumer Vikram V. Kulkarni Hayden H. Ware Fahad Gulraiz Miguel A. Chavez Cavasos Gabriela Martinez Zayas Shradha Wali Andrew P. Rice Hongbing Liu James M. Tour William K. A. Sikkema Ana S. Cruz Solbes Keith A. Youker Michael J. Tuvim Burton F. Dickey Scott E. Evans |
| author_sort |
Carson T. Kirkpatrick |
| title |
Inducible Lung Epithelial Resistance Requires Multisource Reactive Oxygen Species Generation To Protect against Viral Infections |
| title_short |
Inducible Lung Epithelial Resistance Requires Multisource Reactive Oxygen Species Generation To Protect against Viral Infections |
| title_full |
Inducible Lung Epithelial Resistance Requires Multisource Reactive Oxygen Species Generation To Protect against Viral Infections |
| title_fullStr |
Inducible Lung Epithelial Resistance Requires Multisource Reactive Oxygen Species Generation To Protect against Viral Infections |
| title_full_unstemmed |
Inducible Lung Epithelial Resistance Requires Multisource Reactive Oxygen Species Generation To Protect against Viral Infections |
| title_sort |
inducible lung epithelial resistance requires multisource reactive oxygen species generation to protect against viral infections |
| publisher |
American Society for Microbiology |
| publishDate |
2018 |
| url |
https://doaj.org/article/bad5b71e30944f789382fafb101c7a34 |
| work_keys_str_mv |
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| _version_ |
1718426992348495872 |