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Influenza A virus remains a major threat to public health worldwide after its first pandemic. Scientists keep searching novel anti-influenza drugs, of which natural products present to be an important source. Myricetin, a natural flavonol compound, which exists in many edible plants, which has a wide range of biological activities, but its anti-influenza A virus activity is ambiguous. This study aims to evaluate the antiinfluenza activity of myricetin and elucidate its underlying mechanism. Our results demonstrated that myricetin could significantly inhibit influenza A virus replication, reduce viral polymerase activity via selective inhibition of viral PB2 subunit, and the production of inflammatory cytokines by inhibiting TLR3 signaling pathway. The binding affinity analysis and the result of molecular docking revealed that myricetin interacted with the PB2 cap-binding pocket of influenza A virus. The above results suggested myricetin could exhibit anti-influenza virus activity with low cytotoxicity as well, and myricetin had low toxicity in BALB/c mice in vivo. Results from this study highlighted myricetin could be considered as a promising anti-influenza virus agent with dual inhibition profile. Furthermore, the compound with similar structure would provide a new option for the development of novel inhibitors against influenza A virus.

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Tumor necrosis factor receptor-associated factor 3 (TRAF3) is one of the intracellular adaptor proteins for the innate immune response, which is involved in signaling regulation in various cellular processes, including the immune responses defending against invading pathogens. However, the defense mechanism of TRAF3 against influenza virus infection remains elusive. In this study, we found that TRAF3 could positively regulate innate antiviral response. Overexpression of TRAF3 significantly enhanced virus-induced IRF3 activation, IFN-β production, and antiviral response, while TRAF3 knockdown promoted influenza A virus replication. Moreover, we clarified that inhibiting ubiquitinated degradation of TRAF3 was associated with anti-influenza effect, thereby facilitating antiviral immunity upon influenza A virus infection. We further demonstrated the key domains of TRAF3 involved in anti-influenza effect. Taken together, these results suggested that TRAF3 performs a vital role in host defense against influenza A virus infection by the type-I IFN signaling pathway. Our findings provide insights into the development of drugs to prevent TRAF3 degradation, which could be a novel therapeutic approach for treatment of influenza A virus infection.