Human long noncoding RNA,VILMIR,is induced by major respiratory viral infections and modulates the host interferon response

Abstract

ABSTRACTLong 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 datasets. Using bulk RNA-sequencing (RNA-seq) analysis, we identified a previously uncharacterized lncRNA, named virus inducible lncRNA modulator of interferon response (VILMIR), that was consistently upregulated afterin vitroinfluenza infection across multiple human epithelial cell lines and influenza A virus subtypes.VILMIRwas also upregulated after SARS-CoV-2 and RSV infectionsin vitro. We experimentally confirmed the response ofVILMIRto influenza infection and interferon-beta (IFN-β) treatment in the A549 human epithelial cell line and found the expression ofVILMIRwas robustly induced by IFN-β treatment in a dose and time-specific manner. Single cell RNA-seq analysis of bronchoalveolar lavage fluid (BALF) samples from COVID-19 patients uncovered thatVILMIRwas upregulated across various cell types including at least five immune cells. The upregulation ofVILMIRin 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 ofVILMIRexpression reduced the magnitude of host transcriptional responses to IFN-β treatment in A549 cells. Together, our results show thatVILMIRis 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,VILMIR, is upregulated after major respiratory viral infections including influenza, SARS-CoV-2, and RSV. We demonstrated thatVILMIRis an interferon-stimulated gene that is upregulated after interferon-beta (IFN-β) in several human cell types. We also found that knockdown ofVILMIRreduced the magnitude of host transcriptional responses to IFN-β treatment in human epithelial cells. Our results reveal thatVILMIRregulates the host interferon response and may present a new therapeutic target during human respiratory viral infections.