Nguyen Thuy Thu, Suzuki Shoichi, Sugamata Ryuichi, Ito Fuyu, Tran Dat Huu, Yamamoto Tomoko, Kawachi Shoji, Suzuki Kazuo
Department of Health Protection, Graduate School of Medicine, Teikyo University.
Asia International Institute of Infectious Disease Control, Teikyo University.
Tohoku J Exp Med. 2018 Jun;245(2):131-140. doi: 10.1620/tjem.245.131.
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.
模式识别受体可识别RNA病毒，并触发I型和III型干扰素（IFN）的产生以及细胞凋亡，以限制病毒的复制和传播。一些先天免疫细胞会在病毒感染后产生氧化剂，以抵御病毒入侵。最近的研究表明，次硫氰酸（HOSCN）具有杀病毒活性，它是由过氧化物酶催化硫氰酸盐与过氧化氢反应生成的一种氧化剂。然而，HOSCN对宿主抗病毒反应的影响仍不清楚。在本研究中，我们旨在使用病毒RNA模拟物聚肌苷酸-聚胞苷酸（polyI:C）来阐明HOSCN在气道上皮细胞针对RNA病毒的宿主抗病毒反应中的作用。我们的结果表明，HOSCN抑制了NCI-H292人气道上皮细胞中的抗病毒反应。HOSCN减少了polyI:C诱导的细胞凋亡以及IFNB1、IFNL1、IFNL2和IFNL3 mRNA的表达水平。此外，HOSCN还抑制了其他干扰素调节因子3（IRF3）依赖性基因的诱导。进一步针对IRF3的分析表明，HOSCN通过抑制TANK结合激酶1（TBK1）的磷酸化，抑制了IRF3在Ser386和Ser396位点的磷酸化及其二聚化和核转位。此外，HOSCN导致IRF3在Ser386和Ser396以外的位点发生磷酸化，这意味着HOSCN可能会导致IRF3的构象变化，从而损害其功能。总的来说，这些结果表明，HOSCN在抗病毒反应中发挥了新的信号作用，作为细胞凋亡和TBK1-IRF3信号通路的负调节因子，限制了IRF3依赖性基因的表达。
