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• W2556048595 abstract "Reactive oxygen species (ROS) promote influenza pathogenicity by an unknown mechanism. Our aims were to determine 1) the site and enzymatic source of subcellular ROS generation and 2) the impact of ROS on the pathogenesis of virus infection. To do this, confocal microscopy was used to assess the subcellular distribution of viruses, toll-like receptors (TLRs) and NOX2, and to assess endosomal ROS production in human and mouse macrophages infected with various ssRNA, dsRNA and dsDNA viruses. Mice were infected intranasally with influenza A virus (Hong Kong X-31 strain, 10 5 PFUs) for assessments of airway inflammation, viral titers, cytokine expression and serum antibody levels. Site-directed mutagenesis was used to mutate cysteine residues to alanine on TLR7 for assessments of oxidatively modified receptor. Evidently, NOX2 co-located with virus and TLR7 resulting in an increase in endosomal ROS production after the internalization of the ssRNA and DNA viruses into endocytic compartments. NOX2 oxidase activation was dependent on endosomal acidification and the engagement of TLR7 for ssRNA viruses or TLR9 for DNA viruses. NOX2-dependent endosomal H 2 O 2 caused modification of crucial cysteine residues on the ectodomain of TLR7, resulting in suppression of anti-viral cytokine expression. Genetic deletion or pharmacological inhibition of NOX2 significantly suppressed airway inflammation and viral titers following influenza A virus infection. Also, serum and airway IgA and total IgG were significantly higher in NOX2 -/y mice compared to control. In conclusion, activation of endosomal NOX2 oxidase suppresses fundamental components of viral immunity, and this has major implications for the treatment of virus infections." @default.
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• W2556048595 date "2016-09-01" @default.
• W2556048595 modified "2023-09-22" @default.
• W2556048595 title "NOX2 oxidase expressed in endosomes exacerbates influenza pathogenicity" @default.
• W2556048595 doi "https://doi.org/10.1183/13993003.congress-2016.pa2600" @default.
• W2556048595 hasPublicationYear "2016" @default.
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