Influenza Non-structural Protein 1 (NS1)-Induced Read-through Transcription Produces MicroRNA-146a to Modulate Viral Replication and Immune Response

Abstract

<p><strong>Background: </strong>Mir-146a, a microRNA known to be induced upon infection by various viruses, plays a significant role in the cellular response to influenza infection. Originally, it has been suggested that it supports viral replication, however miR-146a also exerts a protective role during influenza virus infection. This uncovers its importance for further studies and evaluations as a potential therapeutic target for influenza. Although the role of miR-146a in other viruses has been extensively studied, it is poorly understood how miR-146a is generated during influenza infection. Therefore, we will be looking to identify the mechanisms behind miR-146a generation.</p><p><strong>Methods: </strong>Here, we combined RNA seq analysis with bioinformatics approach to uncover the role of miR-146a in influenza and the mechanism of miR146a production.</p><p><strong>Results: </strong>Our study found that during influenza virus infection, miR146a suppresses IRAK1 and TRAF6 expression, which impedes type I interferon (IFN) signaling pathway and thereby promotes viral replication. Concurrently, using a highly pathogenic avian influenza (HPAI) infection mouse model, we showed that miR146a also modulates the inflammatory response and alleviates the cytokine storm, a severe immune reaction that is detrimental to the host. Multiple transcription factors have been implicated in the activation of miR-146a transcription during viral infections. However, our findings reveal that miR-146a induction occurs via the influenza NS1 protein and its expression is generated through NS1-induced readthrough transcription, independent of NF-κB regulation, which was observed in other viral infections. Depletion of BRD4 or CPSF30, which have essential roles in transcriptional elongation and 3'-RNA processing, or mutation of NS1 associated with these factors, impedes NS1-mediated readthrough transcription, resulting in reduced miR146a expression.</p><p><strong>Conclusion: </strong>Our results highlight how the influenza NS1 protein manipulates the host's epigenetic machinery to benefit its survival and provide insights into the intricate interaction between viral infection and host response.</p>