Journal article

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 RS Broughton, Malcolm R Starkey, Renee van der Sluis, Sharon R Lewin, Steven Bozinovski, Luke AJ O'Neill, Tim Quach, Christopher JH Porter, Doug A Brooks, John J O'Leary, Stavros Selemidis

NATURE COMMUNICATIONS | NATURE PUBLISHING GROUP | Published : 2017

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 netw..

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Grants

Awarded by Australian Research Council (ARC)


Awarded by National Health and Medical Research Council of Australia (NHMRC)


Awarded by NHMRC


Awarded by ARC Centre of Excellence in Bio-Nano Science and Technology


Funding Acknowledgements

This work was supported by the Australian Research Council (ARC) Future Fellowship Scheme for S.S. (I.D. FT120100876) and S.B. (I.D. FT130100654); The National Health and Medical Research Council of Australia (NHMRC) RD Wright Fellowship scheme for M.L.H. (I.D. 1061687); The NHMRC Senior Research Fellowship Scheme for G.R.D. (I.D. 1006017) and C.G.S. (I.D. 1079467), The NHMRC practitioner fellowship for S.R.L. (I.D. 1042654); The NHMRC Early Career Fellowship for M.R.S. (I.D. 1072000); The NHMRC project grant schemes (Project I.D. 1122506, 1128276, 1027112, 1041795, 1052979); the ARC Centre of Excellence in Bio-Nano Science and Technology (Project CE140100036) and The Australian Postgraduate Award for E.E.T. The authors acknowledge the Monash Micro-Imaging facility (provision of instrumentation and training). The authors also wish to thank the following people for providing viruses including Associate Prof. Elizabeth McGraw (Monash University); A/Prof. Barbara Coulson (The Peter Doherty Institute for Infection and Immunity, The University of Melbourne); Dr Ashley Mansell (Hudson Institute of Medical Research, Monash University), Dr Niahm Mangan (Hudson Institute of Medical Research, Monash University), A/Prof David Tscharke (Australia National University), Prof Sharon Lewin (The Peter Doherty Institute for Infection and Immunity, The University of Melbourne) and A/Prof John Stambas (CSIRO, Deakin University, Geelong, Australia). We thank Prof Karlheinz Peter (Baker IDI Heart and Diabetes Institute, Melbourne, Australia) for providing TLR9<SUP>-/-</SUP> mice and Prof Philip Hansbro (Hunter Medical School, University of Newcastle, Australia) for TLR7<SUP>-/-</SUP> mice. Also the authors wish to thank Prof Arthur Christopoulos (Drug Discovery Biology, Monash institute of Pharmaceutical Sciences, Monash University, Australia) for providing feedback on the manuscript and Ms Felicia Liong (School of Health and Biomedical Sciences, RMIT University) for proof reading the manuscript.