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 interferon-β (IFN-β)-mediated innate immunity, as lncRNA-155-deficient mice exhibits a unique transcriptional signature characterized by the downregulation of IAV-induced 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.

To Cite This Article: Shrestha P, Zhang Q, Gao S, Wang Y, Wen F, Li Y, Sajjad N, Huang S, Rai KR and Chen JL, 2026. Induction of HAMP by influenza a virus in the LncRNA-155-deficient host contributes to suppression of antiviral innate immunity. Pak Vet J, 46(8): 1906-1919. http://dx.doi.org/10.29261/pakvetj/2026.184