IAV inhibits the host antiviral defense mediated by LncRNA-LRIR to enhance viral replication.

Long non-coding RNAs (lncRNAs) are defined as transcripts longer than 200 nucleotides(nt) with no protein-coding potential. Accumulating evidence indicates that the interaction between lncRNAs and influenza A virus (IAV) plays an crucial role in multiple biological processes, including host antiviral immunity and regulating viral replication. However, the mechanisms by which IAV resists antiviral immunity and enhances its replication by inhibiting lncRNA-mediated antiviral defense remain largely unexplored. In this study, we identified a lncRNA, designated LRIR (LncRNA Regulating IAV Replication), which is significantly downregulated upon IAV infection in A549 cells. Notably, LRIR knockdown significantly promotes IAV replication, whereas LRIR overexpression inhibits viral replication, suggesting that LRIR exerts its antiviral effect during IAV infection. Furthermore, the antiviral activity of LRIR primarily depends on the regions spanning from 258 to 381 nt and 38-97 nt. Mechanistically, LRIR was found to inhibit replication and transcription of the viral genome. Further studies indicated that LRIR suppresses IAV replication by downregulating the expression of transmembrane protease serine 2 (TMPRSS2). Collectively, our findings reveal that IAV infection suppresses LRIR expression, thereby weakening its negative regulation of TMPRSS2 and subsequently promoting viral replication. These results provide a theoretical foundation for the development of novel anti-IAV therapeutics.