Dual oxidase 1 promotes antiviral innate immunity

Demba Sarr, Aaron D. Gingerich, Nuha Milad Asthiwi, Faris Almutairi, Giuseppe A. Sautto, Jeffrey Ecker, Tamás Nagy, Matthew B. Kilgore, Joshua D. Chandler, Ted M. Ross, Ralph A. Tripp, Balázs Rada

Research output: Contribution to journalArticlepeer-review

16 Citations (Scopus)

Abstract

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.

Original languageEnglish
Article numbere2017130118
Pages (from-to)1-10
Number of pages10
JournalProceedings of the National Academy of Sciences of the United States of America
Volume118
Issue number26
DOIs
Publication statusPublished - 29 Jun 2021
Externally publishedYes

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