Ye Sichao, Liang Yisha, Chang Yu, Lai Bailiang, Zhong Jin
CAS Key Laboratory of Molecular Virology and Immunology, Shanghai Institute of Immunity and Infection, Chinese Academy of Sciences, Shanghai, China.
Savaid Medical School, University of Chinese Academy of Sciences, Beijing, China.
J Med Virol. 2025 Feb;97(2):e70194. doi: 10.1002/jmv.70194.
RIG-I like receptors (RLRs) are a family of cytosolic RNA sensors that sense RNA virus infection to activate innate immune response. It is generally believed that different RNA viruses are recognized by either RIG-I or MDA5, two important RLR members, depending on the nature of pathogen-associated molecular patterns (PAMPs) that are generated by RNA virus replication. Dengue virus (DENV) is an important RNA virus causing serious human diseases. Despite extensive investigations, the molecular basis of the DENV PAMP recognized by the host RLR has been poorly defined. Here, we demonstrated that the DENV infection-induced interferon response is dependent upon both RIG-I and MDA5, with RIG-I playing a predominant role. Next we purified the DENV PAMP RNA from the DENV-infected cells, and demonstrated that the purified DENV PAMP is viral full-length double-stranded RNA bearing 5'ppp modifications, likely representing the viral replicative-form RNA. Finally, we confirmed the nature of the DENV PAMP by reconstituting the viral replicative-form RNA from in vitro synthesized DENV genomic RNA. In conclusion, our work not only defined the molecular basis of the RLR-PAMP interaction during DENV infection, but also revealed the previously underappreciated recognition of a distinct moiety of the same PAMP by different RLRs in innate immunity against RNA viruses.
视维样受体（RLRs）是一类胞质RNA传感器家族，可感知RNA病毒感染以激活先天免疫反应。一般认为，不同的RNA病毒由视维样受体（RIG-I）或黑色素瘤分化相关基因5（MDA5）这两个重要的RLR成员识别，这取决于RNA病毒复制产生的病原体相关分子模式（PAMPs）的性质。登革病毒（DENV）是一种导致严重人类疾病的重要RNA病毒。尽管进行了广泛研究，但宿主RLR识别的DENV PAMP的分子基础仍不清楚。在这里，我们证明了DENV感染诱导的干扰素反应依赖于RIG-I和MDA5，其中RIG-I起主要作用。接下来，我们从感染DENV的细胞中纯化了DENV PAMP RNA，并证明纯化的DENV PAMP是带有5'ppp修饰的病毒全长双链RNA，可能代表病毒复制形式的RNA。最后，我们通过从体外合成的DENV基因组RNA重建病毒复制形式的RNA，证实了DENV PAMP的性质。总之，我们的工作不仅确定了DENV感染期间RLR-PAMP相互作用的分子基础，还揭示了在针对RNA病毒的先天免疫中，不同RLR对同一PAMP的一个不同部分的先前未被充分认识的识别。
