Human long noncoding RNA <i>VILMIR</i> is induced by major respiratory viral infections and modulates the host interferon response

Long noncoding RNAs (lncRNAs) are a newer class of noncoding transcripts identified as key regulators of biological processes. Here, we aimed to identify novel lncRNA targets that play critical roles in major human respiratory viral infections by systematically mining large-scale transcriptomic data sets. Using bulk RNA-sequencing (RNA-seq) analysis, we identified a previously uncharacterized lncRNA, named virus-inducible lncRNA modulator of interferon response (<i>VILMIR</i>), that was consistently upregulated after <i>in vitro</i> influenza infection across multiple human epithelial cell lines and influenza A virus subtypes. <i>VILMIR</i> was also upregulated after severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) and respiratory syncytial virus (RSV) infections <i>in vitro</i>. We experimentally confirmed the response of <i>VILMIR</i> to influenza infection and interferon-beta (IFN-β) treatment in the A549 human epithelial cell line and found the expression of <i>VILMIR</i> was robustly induced by IFN-β treatment in a dose- and time-specific manner. Single-cell RNA-seq analysis of bronchoalveolar lavage fluid samples from coronavirus disease 2019 (COVID-19) patients uncovered that <i>VILMIR</i> was upregulated across various cell types, including at least five immune cells. The upregulation of <i>VILMIR</i> in immune cells was further confirmed in the human T cell and monocyte cell lines, SUP-T1 and THP-1, after IFN-β treatment. Finally, we found that knockdown of <i>VILMIR</i> expression reduced the magnitude of host transcriptional responses to both IFN-β treatment and influenza A virus infection in A549 cells. Together, our results show that <i>VILMIR</i> is a novel interferon-stimulated gene (ISG) that regulates the host interferon response and may be a potential therapeutic target for human respiratory viral infections upon further mechanistic investigation.IMPORTANCEIdentifying host factors that regulate the immune response to human respiratory viral infection is critical to developing new therapeutics. Human long noncoding RNAs (lncRNAs) have been found to play key regulatory roles during biological processes; however, the majority of lncRNA functions within the host antiviral response remain unknown. In this study, we identified that a previously uncharacterized lncRNA, virus-inducible lncRNA modulator of interferon response (<i>VILMIR</i>), is upregulated after major respiratory viral infections including influenza, severe acute respiratory syndrome coronavirus 2, and respiratory syncytial virus. We demonstrated that <i>VILMIR</i> is an interferon-stimulated gene that is upregulated after interferon-beta (IFN-β) in several human cell types. We also found that knockdown of <i>VILMIR</i> reduced the magnitude of host transcriptional responses to IFN-β treatment and influenza A infection in human epithelial cells. Our results reveal that <i>VILMIR</i> regulates the host interferon response and may present a new therapeutic target during human respiratory viral infections.