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Innate immunity induced by composition-dependent RIG-I recognition of hepatitis C virus RNA

机译：成分依赖性RIG-I识别丙型肝炎病毒RNA诱导的先天免疫

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摘要

Innate immune defences are essential for the control of virus infection and are triggered through host recognition of viral macromolecular motifs known as pathogen-associated molecular patterns (PAMPs). Hepatitis C virus (HCV) is an RNA virus that replicates in the liver, and infects 200 million people worldwide. Infection is regulated by hepatic immune defences triggered by the cellular RIG-I helicase. RIG-I binds PAMP RNA and signals inter-feron regulatory factor 3 activation to induce the expression of interferon-α/β and antiviral/interferon-stimulated genes (ISGs) that limit infection. Here we identify the polyuridine motif of the HCV genome 3' non-translated region and its replication intermediate as the PAMP substrate of RIG-I, and show that this and similar homopolyuridine or homopolyriboadenine motifs present in the genomes of RNA viruses are the chief feature of RIG-I recognition and immune triggering in human and murine cells. 5' terminal triphosphate on the PAMP RNA was necessary but not sufficient for RIG-I binding, which was primarily dependent on homopolymeric ribonucleotide composition, linear structure and length. The HCV PAMP RNA stimulated RIG-I-dependent signalling to induce a hepatic innate immune response in vivo, and triggered interferon and ISG expression to suppress HCV infection in vitro. These results provide a conceptual advance by defining specific homopolymeric RNA motifs within the genome of HCV and other RNA viruses as the PAMP substrate of RIG-I, and demonstrate immunogenic features of the PAMP-RIG-I interaction that could be used as an immune adjuvant for vaccine and immunotherapy approaches.
机译：先天性免疫防御对于控制病毒感染至关重要，是通过宿主识别病毒大分子基序（称为病原体相关分子模式（PAMP））触发的。丙型肝炎病毒（HCV）是一种可在肝脏中复制的RNA病毒，全球感染2亿人。感染受细胞RIG-I解旋酶触发的肝免疫防御作用的调节。 RIG-I结合PAMP RNA并发出干扰素调节因子3激活信号，以诱导干扰素-α/β以及限制感染的抗病毒/干扰素刺激基因（ISG）的表达。在这里，我们确定了HCV基因组3'非翻译区的聚尿苷基序及其复制中间体，作为RIG-I的PAMP底物，并表明存在于RNA病毒基因组中的这种和类似的同聚尿苷或同聚核糖腺嘌呤基序是主要特征和鼠细胞中RIG-I识别和免疫触发的研究。 PAMP RNA上的5'末端三磷酸酯是必需的，但不足以进行RIG-1结合，这主要取决于均聚物核糖核苷酸的组成，线性结构和长度。 HCV PAMP RNA刺激RIG-I依赖性信号传导，在体内诱导肝固有免疫反应，并触发干扰素和ISG表达抑制体外HCV感染。这些结果通过定义HCV和其他RNA病毒的基因组内特定的均聚RNA基序作为RIG-I的PAMP底物，提供了概念上的进展，并证明了可用作免疫佐剂的PAMP-RIG-I相互作用的免疫原性特征用于疫苗和免疫疗法。

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