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Renée Marije van der Sluis

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

Publikation: Bidrag til tidsskrift/Konferencebidrag i tidsskrift /Bidrag til avisTidsskriftartikelForskningpeer review

DOI

  • Eunice E To, Department of Pharmacology, Infection and Immunity Program, Biomedicine Discovery Institute, Monash University, Clayton, Victoria, 3800, Australia.
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  • Ross Vlahos, Program in Chronic Infectious and Inflammatory Diseases, School of Health and Biomedical Sciences, College of Science, Engineering & Health, RMIT University, Bundoora, Victoria, 3083, Australia.
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  • Raymond Luong, Department of Pharmacology, Infection and Immunity Program, Biomedicine Discovery Institute, Monash University, Clayton, Victoria, 3800, Australia.
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  • Michelle L Halls, Drug Discovery Biology, Monash Institute of Pharmaceutical Sciences, Monash University, Parkville, Victoria 3052 Australia
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  • Patrick C Reading, Department of Microbiology and Immunology, The University of Melbourne, The Peter Doherty Institute for Infection and Immunity, Melbourne, Victoria 3000 Australia
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  • Paul T King, Monash Lung and Sleep, Department of Medicine, Monash Medical Centre, Monash University, Clayton, Victoria 3168 Australia
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  • Christopher Chan, Center for Systems Biology, Massachusetts General Hospital, Harvard Medical School, 185 Cambridge Street, Boston, Massachusetts 02114 USA
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  • Grant R Drummond, La Trobe University
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  • Christopher G Sobey, La Trobe University
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  • Brad R S Broughton, Department of Pharmacology, Infection and Immunity Program, Biomedicine Discovery Institute, Monash University, Clayton, Victoria, 3800, Australia.
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  • Malcolm R Starkey, Priority Research Centre's Grow Up Well and Healthy Lungs, School of Biomedical Sciences and Pharmacy, Faculty of Health and Medicine, The University of Newcastle, and Hunter Medical Research Institute, New South Wales, 2305, Australia.
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  • Renee van der Sluis
  • Sharon R Lewin, Department of Infectious Diseases, Alfred Hospital and Monash University, Melbourne, 3004 Australia , The Peter Doherty Institute for Infection and Immunity, The University of Melbourne, VIC, AUS.
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  • Steven Bozinovski, Program in Chronic Infectious and Inflammatory Diseases, School of Health and Biomedical Sciences, College of Science, Engineering & Health, RMIT University, Bundoora, Victoria, 3083, Australia.
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  • Luke A J O'Neill, School of biochemistry and Immunology, Trinity Biomedical Sciences Institute, Trinity College, College Green, Dublin 2, D02 PN40, Ireland, UK.
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  • Tim Quach, Drug Delivery Disposition and Dynamics, Monash Institute of Pharmaceutical Sciences, Monash University, Parkville, Victoria 3052 Australia
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  • Christopher J H Porter, Drug Delivery Disposition and Dynamics, Monash Institute of Pharmaceutical Sciences, Monash University, Parkville, Victoria 3052 Australia
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  • Doug A Brooks, School of Pharmacy and Medical Sciences, Sansom Institute for Health Research, Division of Health Sciences, University of South Australia, Adelaide, 5001 Australia
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  • John J O'Leary, Molecular Pathology Laboratory, The Coombe Women and Infants University Hospital, Dublin 8, Ireland.
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  • Stavros Selemidis, Department of Pharmacology, Infection and Immunity Program, Biomedicine Discovery Institute, Monash University, Clayton, Victoria, 3800, Australia. Stavros.selemidis@RMIT.edu.au.

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.

OriginalsprogEngelsk
TidsskriftNature Communications
Vol/bind8
Nummer1
Sider (fra-til)69
ISSN2041-1723
DOI
StatusUdgivet - 12 jul. 2017
Eksternt udgivetJa

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