Endosomal NOX2 oxidase exacerbates virus pathogenicity and is a target for antiviral therapy

Eunice E. To, Ross Vlahos, Raymond Luong, Michelle L. Halls, Patrick C Reading, Paul T. King, Christopher Chan, Grant R. Drummond, Christopher G. Sobey, Bradley R.S. Broughton, Malcolm R Starkey, Renee van der Sluis, Sharon R. Lewin, Steven Bozinovski, Luke A J O'Neill, Tim Quach, Christopher J.H. Porter, Doug A. Brooks, John O'Leary, Stavros Selemidis

Research output: Contribution to journalArticleResearchpeer-review

Abstract

The imminent threat of viral epidemics and pandemics dictates a need for therapeutic approaches that target viral pathology irrespective of the infecting strain. Reactive oxygen species are ancient processes that protect plants, fungi and animals against invading pathogens including bacteria. However, in mammals reactive oxygen species production paradoxically promotes virus pathogenicity by mechanisms not yet defined. Here we identify that the primary enzymatic source of reactive oxygen species, NOX2 oxidase, is activated by single stranded RNA and DNA viruses in endocytic compartments resulting in endosomal hydrogen peroxide generation, which suppresses antiviral and humoral signaling networks via modification of a unique, highly conserved cysteine residue (Cys98) on Toll-like receptor-7. Accordingly, targeted inhibition of endosomal reactive oxygen species production abrogates influenza A virus pathogenicity. We conclude that endosomal reactive oxygen species promote fundamental molecular mechanisms of viral pathogenicity, and the specific targeting of this pathogenic process with endosomal-targeted reactive oxygen species inhibitors has implications for the treatment of viral disease.

Original languageEnglish
Article number69
Number of pages17
JournalNature Communications
Volume8
Issue number1
DOIs
Publication statusPublished - 1 Dec 2017

Keywords

  • influenza virus
  • recombinant peptide therapy
  • toll-like receptors
  • viral pathogenesis

Cite this

To, Eunice E. ; Vlahos, Ross ; Luong, Raymond ; Halls, Michelle L. ; Reading, Patrick C ; King, Paul T. ; Chan, Christopher ; Drummond, Grant R. ; Sobey, Christopher G. ; Broughton, Bradley R.S. ; Starkey, Malcolm R ; van der Sluis, Renee ; Lewin, Sharon R. ; Bozinovski, Steven ; O'Neill, Luke A J ; Quach, Tim ; Porter, Christopher J.H. ; Brooks, Doug A. ; O'Leary, John ; Selemidis, Stavros. / Endosomal NOX2 oxidase exacerbates virus pathogenicity and is a target for antiviral therapy. In: Nature Communications. 2017 ; Vol. 8, No. 1.
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abstract = "The imminent threat of viral epidemics and pandemics dictates a need for therapeutic approaches that target viral pathology irrespective of the infecting strain. Reactive oxygen species are ancient processes that protect plants, fungi and animals against invading pathogens including bacteria. However, in mammals reactive oxygen species production paradoxically promotes virus pathogenicity by mechanisms not yet defined. Here we identify that the primary enzymatic source of reactive oxygen species, NOX2 oxidase, is activated by single stranded RNA and DNA viruses in endocytic compartments resulting in endosomal hydrogen peroxide generation, which suppresses antiviral and humoral signaling networks via modification of a unique, highly conserved cysteine residue (Cys98) on Toll-like receptor-7. Accordingly, targeted inhibition of endosomal reactive oxygen species production abrogates influenza A virus pathogenicity. We conclude that endosomal reactive oxygen species promote fundamental molecular mechanisms of viral pathogenicity, and the specific targeting of this pathogenic process with endosomal-targeted reactive oxygen species inhibitors has implications for the treatment of viral disease.",
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Endosomal NOX2 oxidase exacerbates virus pathogenicity and is a target for antiviral therapy. / To, Eunice E.; Vlahos, Ross; Luong, Raymond; Halls, Michelle L.; Reading, Patrick C; King, Paul T.; Chan, Christopher; Drummond, Grant R.; Sobey, Christopher G.; Broughton, Bradley R.S.; Starkey, Malcolm R; van der Sluis, Renee ; Lewin, Sharon R.; Bozinovski, Steven; O'Neill, Luke A J; Quach, Tim; Porter, Christopher J.H.; Brooks, Doug A.; O'Leary, John; Selemidis, Stavros.

In: Nature Communications, Vol. 8, No. 1, 69, 01.12.2017.

Research output: Contribution to journalArticleResearchpeer-review

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AU - Reading, Patrick C

AU - King, Paul T.

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AU - Bozinovski, Steven

AU - O'Neill, Luke A J

AU - Quach, Tim

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AU - Selemidis, Stavros

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