Dual oxidase 1 promotes antiviral innate immunity

• Published in: Proceedings of the National Academy of Sciences - PNAS 2021-06, Vol.118 (26), p.1-10
• Main Authors: Sarr, Demba, Gingerich, Aaron D., Asthiwi, Nuha Milad, Almutairi, Faris, Sautto, Giuseppe A., Ecker, Jeffrey, Nagy, Tamás, Kilgore, Matthew B., Chandler, Joshua D., Ross, Ted M., Tripp, Ralph A., Rada, Balázs
• Format: Article
• Language: English
• Subjects: Animals; Antiinfectives and antibacterials; Apoptosis; Biological Sciences; Bronchi - pathology; Bronchi - virology; Catalase; CCL19 protein; CCL20 protein; CCL3 protein; Chemokines; CXCL11 protein; Cytokines; Cytokines - metabolism; Disease Models, Animal; Dual Oxidases - metabolism; Epithelial cells; Epithelial Cells - pathology; Epithelium; Exo-a-sialidase; Humans; Hydrogen peroxide; Hydrogen Peroxide - metabolism; IL-1β; Immune clearance; Immune system; Immunity; Immunity, Innate; Influenza; Influenza, Human - immunology; Influenza, Human - pathology; Influenza, Human - virology; Innate immunity; Interleukin 2; Lactoperoxidase - metabolism; Mice; Morbidity; Morphology; NAD(P)H oxidase; Neuraminidase - chemistry; Neuraminidase - metabolism; Orthomyxoviridae - physiology; Orthomyxoviridae Infections - immunology; Orthomyxoviridae Infections - pathology; Orthomyxoviridae Infections - virology; Oxidase; Peroxidase; Proteolysis; Respiratory tract; RNA, Viral - metabolism; Thiocyanates; Transcription; Viral infections; Viral Proteins - chemistry; Viral Proteins - metabolism; Virus Inactivation; Virus Internalization; Virus Replication; Viruses
• ISSN: 0027-8424; 1091-6490; 1091-6490
• DOI: 10.1073/pnas.2017130118

Dual oxidase 1 (DUOX1) is an NADPH oxidase that is highly expressed in respiratory epithelial cells and produces H₂O₂ in the airway lumen. While a line of prior in vitro observations suggested that DUOX1 works in partnership with an airway peroxidase, lactoperoxidase (LPO), to produce antimicrobial hypothiocyanite (OSCN⁻) in the airways, the in vivo role of DUOX1 in mammalian organisms has remained unproven to date. Here, we show that Duox1 promotes antiviral innate immunity in vivo. Upon influenza airway challenge, Duox1 −/− mice have enhanced mortality, morbidity, and impaired lung viral clearance. Duox1 increases the airway levels of several cytokines (IL-1β, IL-2, CCL1, CCL3, CCL11, CCL19, CCL20, CCL27, CXCL5, and CXCL11), contributes to innate immune cell recruitment, and affects epithelial apoptosis in the airways. In primary human tracheobronchial epithelial cells, OSCN⁻ is generated by LPO using DUOX1-derived H₂O₂ and inactivates several influenza strains in vitro. We also show that OSCN⁻ diminishes influenza replication and viral RNA synthesis in infected host cells that is inhibited by the H₂O₂ scavenger catalase. Binding of the influenza virus to host cells and viral entry are both reduced by OSCN⁻ in an H₂O₂-dependent manner in vitro. OSCN⁻ does not affect the neuraminidase activity or morphology of the influenza virus. Overall, this antiviral function of Duox1 identifies an in vivo role of this gene, defines the steps in the infection cycle targeted by OSCN⁻, and proposes that boosting this mechanism in vivo can have therapeutic potential in treating viral infections.