Induction of HAMP by Influenza A Virus in the LncRNA-155-Deficient Host Contributes to Suppression of Antiviral Innate Immunity

Influenza A virus (IAV) is a major zoonotic respiratory pathogen with persistent pandemic potential.Long non-coding RNAs (lncRNAs) are known to play a critical role in antiviral immunity.Our previous study has identified lncRNA-155, a product of MIR155HG, as a positive regulator of antiviral innate immunity, but the molecular mechanism by which it potentiates immune response remains unclear.Here, RNA-sequencing analysis revealed that lncRNA-155 is critical for interferonβ (IFN-β)-mediated innate immunity, as lncRNA-155-deficient mice exhibits a unique transcriptional signature characterized by the downregulation of IAVinduced expression of IFN-β and a set of interferon-stimulated genes compared to other genotypes.Furthermore, we found that lncRNA-155 functions as a negative regulator of HAMP expression, as evidenced by a robust upregulation of HAMP expression in response to IAV infection in lncRNA-155-deficient animal tissues and cells.Functional analysis showed the profound impact of HAMP on IAV replication.Knockdown of HAMP results in reduced viral replication by enhancing IAV-induced antiviral responses.Conversely, HAMP overexpression promotes IAV replication by suppressing the antiviral responses, as characterized by the significant inhibition of IAV-induced IFN-β production and key interferon-stimulated genes expression.HAMP overexpression also causes the impaired activation of the transcription factors NF-κB and IRF3 following IAV infection.Importantly, forced HAMP expression abrogates the antiviral responses potentiated by lncRNA-155.Together, this study identifies a new lncRNA-155/HAMP axis wherein lncRNA-155 augments antiviral immunity by suppressing HAMP.