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It is generally believed that different RNA viruses are recognized by either RIG\u2010I or MDA5, two important RLR members, depending on the nature of pathogen\u2010associated 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\u2010induced interferon response is dependent upon both RIG\u2010I and MDA5, with RIG\u2010I playing a predominant role. Next we purified the DENV PAMP RNA from the DENV\u2010infected cells, and demonstrated that the purified DENV PAMP is viral full\u2010length double\u2010stranded RNA bearing 5'ppp modifications, likely representing the viral replicative\u2010form RNA. Finally, we confirmed the nature of the DENV PAMP by reconstituting the viral replicative\u2010form RNA from in vitro synthesized DENV genomic RNA. In conclusion, our work not only defined the molecular basis of the RLR\u2010PAMP 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.<\/jats:p>","DOI":"10.1002\/jmv.70194","type":"journal-article","created":{"date-parts":[[2025,1,28]],"date-time":"2025-01-28T12:09:48Z","timestamp":1738066188000},"update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":10,"title":["Dengue Virus Replicative\u2010Form dsRNA Is Recognized by Both RIG\u2010I and MDA5 to Activate Innate Immunity"],"prefix":"10.1002","volume":"97","author":[{"given":"Sichao","family":"Ye","sequence":"first","affiliation":[{"name":"CAS Key Laboratory of Molecular Virology and Immunology, Shanghai Institute of Immunity and Infection Chinese Academy of Sciences Shanghai China"},{"name":"Savaid Medical School University of Chinese Academy of 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