Chhabra Preeti, Ranjan Priya, Cromeans Theresa, Sambhara Suryaprakash, Vinjé Jan
Gastroenteritis and Respiratory Viruses Laboratory Branch, Division of Viral Diseases, National Center for Immunizations and Respiratory Disease, Centers for Disease Control and Prevention, Atlanta, GA, 30329, USA.
Immunology and Pathogenesis Branch, Influenza Division, National Center for Immunizations and Respiratory Disease, Centers for Disease Control and Prevention, Atlanta, GA, 30329, USA.
J Gen Virol. 2017 May;98(5):1016-1026. doi: 10.1099/jgv.0.000769. Epub 2017 May 22.
Human noroviruses are a major cause of acute gastroenteritis worldwide, but the lack of a robust cell culture system or small animal model have hampered a better understanding of innate immunity against these viruses. Tulane virus (TV) is the prototype virus of a tentative new genus, Recovirus, in the family Caliciviridae. Its epidemiology and biological properties most closely resemble human norovirus. The host innate immune response to RNA virus infection primarily involves pathogen-sensing toll-like receptors (TLRs) TLR3 and TLR7 and retinoic acid-inducible gene I-like receptor RIG-I and melanoma differentiation associated gene 5 (MDA5). In this study, by using siRNA knockdown, we report that TV infection in LLC-MK2 cells results in an early [3 h post infection (h p.i.), P<0.05] RIG-I-dependent and type I interferon-mediated antiviral response, whereas an MDA5-mediated antiviral effect was observed at later (12 h p.i.; P<0.05) stages of TV replication. Induction of RIG-I and MDA5 was critical for inhibition of TV replication. Furthermore, pre-activation of the RIG-I/MDA5 pathway prevented TV replication (>900-fold decrease; P<0.05), suggesting that RIG-I and MDA5 ligands could be used to develop novel preventive and therapeutic measures against norovirus.
人诺如病毒是全球急性胃肠炎的主要病因，但缺乏完善的细胞培养系统或小动物模型阻碍了对针对这些病毒的天然免疫的深入了解。图莱纳病毒（TV）是杯状病毒科中一个暂定新属——重组病毒属的原型病毒。其流行病学和生物学特性与人类诺如病毒最为相似。宿主对RNA病毒感染的天然免疫反应主要涉及病原体识别Toll样受体（TLR）TLR3和TLR7以及视黄酸诱导基因I样受体RIG-I和黑色素瘤分化相关基因5（MDA5）。在本研究中，通过使用小干扰RNA（siRNA）敲低技术，我们报告在LLC-MK2细胞中TV感染会导致早期[感染后3小时（h p.i.），P<0.05]依赖RIG-I且由I型干扰素介导的抗病毒反应，而在TV复制的后期（感染后12小时；P<0.05）观察到MDA5介导的抗病毒作用。RIG-I和MDA5的诱导对于抑制TV复制至关重要。此外，RIG-I/MDA5途径的预激活可阻止TV复制（降低>900倍；P<0.05），这表明RIG-I和MDA5配体可用于开发针对诺如病毒的新型预防和治疗措施。
