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

The data that support the findings of this study are available from the corresponding author, Dr Stavros Selemidis, upon request.

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 Q7 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.

本研究所得结论的支撑数据可向通讯作者斯塔夫罗斯·塞莱米迪斯（Stavros Selemidis）博士申请获取。病毒疫情与大流行的迫近威胁，亟需开发无需依赖感染毒株即可靶向病毒致病机制的治疗策略。活性氧（Reactive oxygen species）是一类古老的防御系统，可保护植物、真菌与动物抵御包括细菌在内的入侵病原体。然而在哺乳动物体内，活性氧的产生却反常地（Q7）促进了病毒的致病能力，其具体分子机制尚未阐明。本研究发现，活性氧的主要酶促来源——NADPH氧化酶2（NOX2 oxidase），可在内吞区室中被单链RNA与DNA病毒激活，进而介导内体过氧化氢的生成；后者通过修饰Toll样受体7（Toll-like receptor-7）上一处独特且高度保守的半胱氨酸残基（Cys98），抑制抗病毒与体液信号通路。据此，靶向抑制内体活性氧生成可消除甲型流感病毒的致病能力。本研究结论表明，内体活性氧可促进病毒致病的核心分子机制；采用靶向内体的活性氧抑制剂特异性干预这一致病过程，有望为病毒性疾病的治疗提供新的应用价值。