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, Brad 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 J. O’Leary and Stavros Selemidis ()
Additional contact information
Eunice E. To: School of Health and Biomedical Sciences, College of Science, Engineering & Health, RMIT University
Ross Vlahos: School of Health and Biomedical Sciences, College of Science, Engineering & Health, RMIT University
Raymond Luong: Monash University
Michelle L. Halls: Monash University
Patrick C. Reading: The University of Melbourne, The Peter Doherty Institute for Infection and Immunity
Paul T. King: Monash University
Christopher Chan: Monash University
Grant R. Drummond: School of Life Sciences, La Trobe University
Christopher G. Sobey: School of Life Sciences, La Trobe University
Brad R. S. Broughton: Monash University
Malcolm R. Starkey: The University of Newcastle, and Hunter Medical Research Institute
Renee van der Sluis: The University of Melbourne and Royal Melbourne Hospital
Sharon R. Lewin: The University of Melbourne and Royal Melbourne Hospital
Steven Bozinovski: School of Health and Biomedical Sciences, College of Science, Engineering & Health, RMIT University
Luke A. J. O’Neill: Trinity College Dublin
Tim Quach: Monash University
Christopher J. H. Porter: Monash University
Doug A. Brooks: University of South Australia
John J. O’Leary: Trinity Translational Medicine Institute (TTMI)
Stavros Selemidis: School of Health and Biomedical Sciences, College of Science, Engineering & Health, RMIT University

Nature Communications, 2017, vol. 8, issue 1, 1-17

Abstract: 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.

Date: 2017
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DOI: 10.1038/s41467-017-00057-x

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