Hypothiocyanous Acid Suppresses PolyI:C-Induced Antiviral Responses by Modulating IRF3 Phosphorylation in Human Airway Epithelial Cells

Hypothiocyanous Acid Suppresses PolyI:C-Induced Antiviral Responses by Modulating IRF3 Phosphorylation in Human Airway Epithelial Cells

THUY THU NGUYEN,^1,2 SHOICHI SUZUKI,^1,2 RYUICHI SUGAMATA,^1,2 FUYU ITO,² DAT HUU TRAN,^1,2 TOMOKO YAMAMOTO,² SHOJI KAWACHI² and KAZUO SUZUKI^1,2

¹Department of Health Protection, Graduate School of Medicine, Teikyo University, Tokyo, Japan
²Asia International Institute of Infectious Disease Control, Teikyo University, Tokyo, Japan

Pattern recognition receptors recognize RNA viruses and trigger type I and III interferon (IFN) production and apoptosis to limit viral replication and spread. Some innate immune cells produce oxidants in response to viral infection to protect against invasion. Recent studies have demonstrated the virucidal activity of hypothiocyanous acid (HOSCN), an oxidant generated by the peroxidase-catalyzed reaction of thiocyanate with hydrogen peroxide. However, the effects of HOSCN on host antiviral responses are still unknown. In this study, we aimed to clarify the role of HOSCN in host antiviral responses against RNA viruses in airway epithelial cells using polyinosinic-polycytidylic acid (polyI:C), a mimic of viral RNA. Our results show that HOSCN repressed antiviral responses in NCI-H292 human airway epithelial cells. HOSCN decreased polyI:C-induced apoptosis and the expression levels of IFNB1, IFNL1, IFNL2 and IFNL3 mRNAs. In addition, the induction of other interferon regulatory factor 3 (IRF3)-dependent genes was also suppressed by HOSCN. Further analyses focused on IRF3 revealed that HOSCN inhibited the phosphorylation of IRF3 at Ser386 and Ser396 as well as its dimerization and nuclear translocation by inhibiting the phosphorylation of TANK-binding kinase 1 (TBK1). Furthermore, HOSCN led to the phosphorylation of IRF3 at residues other than Ser386 and Ser396, implying that HOSCN may cause a conformational change in IRF3 to impair its function. Collectively, these results suggest that HOSCN plays a novel signaling role in the antiviral response, acting as a negative regulator of apoptotic and TBK1-IRF3 signaling pathways and limiting IRF3-dependent gene expression.

keywords —— antiviral responses; hypothiocyanous acid; interferon regulatory factor 3; lactoperoxidase; myeloperoxidase

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Tohoku J. Exp. Med., 2018, 245, 131-140

Correspondence: Shoichi Suzuki, Department of Health Protection, Graduate School of Medicine and Asia International Institute of Infectious Disease Control, Teikyo University, Kaga 2-11-1, Itabashi-ku, Tokyo 173-8605, Japan.

e-mail: shoichi3@med.teikyo-u.ac.jp