Journal Article

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

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

2017

Overview

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. Production of reactive oxygen species is an ancient antimicrobial mechanism, but its role in antiviral defense in mammals is unclear. Here, To et al. show that virus infection activates endosomal NOX2 oxidase and restricts TLR7 signaling, and that an endosomal NOX2 inhibitor decreases viral pathogenicity.

• Publisher: Nature Publishing Group UK,Nature Portfolio
• Subject: 631/154/51/2313 / 631/326/596/2555 / 692/420/2780/262/2106/2108 / 692/699/255/1578 / Animals / Antiviral Agents - therapeutic use / Disease Progression / Endosomes - metabolism / Enzyme Inhibitors - pharmacology / Enzyme Inhibitors - therapeutic use / Humanities and Social Sciences / Influenza A virus - drug effects / Influenza A virus - pathogenicity / Membrane Glycoproteins - metabolism / Mice / multidisciplinary / NADPH Oxidase 2 - antagonists & inhibitors / NADPH Oxidase 2 - genetics / NADPH Oxidase 2 - metabolism / Orthomyxoviridae Infections - drug therapy / Orthomyxoviridae Infections - metabolism / Orthomyxoviridae Infections - virology / Reactive Oxygen Species - metabolism / Science / Science (multidisciplinary) / Signal Transduction / Toll-Like Receptor 7 - metabolism / Virulence