Identification of lncRNA-up4 as an Enhancer of Influenza A Virus Replication through Negatively Regulating the Innate Immune Response

Inflammation cause a critical role against immune response and activate the macrophages. Current studies have reported that long non coding RNAs (lncRNAs) regulate the gene expression by interacting with various biological molecules. Experimental research has provided insights into the functions of lncRNAs that have significant impact on host-virus dynamics, including response to IAV infections such as H9N2, WSN, and PR8.Given the global health threat posed by influenza A virus (IAV) and its association with severe pneumonia, we investigated the role of host lncRNAs in IAV infection and pathogenesis. RNA microarray analysis of chicken DF1 cells showed regulation changes in 2,118 lncRNAs following 12 hours of IAV infection (H9N2-VS-CON P-value<0.05 & |log2FC| >1). Notably, lncRNA-up4 exhibited significant up regulation post-IAV induction and was associated with IL-6, a critical cytokine involved in excessive inflammatory response to IAV. Functional analysis of lncRNA-up4 revealed that its depletion resulted in decreased viral NP protein accumulation and reduced IL-6, TNFa, IL-1ß levels, while increasing IFN-ß, MX1, and OAS-1 mRNA expression. Conversely, overexpression of lncRNA-up4 led to increase IL-6, TNF-a, IL-1ß, and decreased IFN-ß, MX1, and OAS-1 levels. In conclusion, lncRNA-up4 modulates cytokines activity and inflammatory responses, providing insights into its regulatory role in innate immunity and interferon response against H9N2 IAV. This research enhances our understanding of the lncRNA-up4 regulatory network and its potential implication in inflammatory diseases. Overall design: to investigate the role of novel lncRNAs in chicken DF-1 cells during H9N2 infection