lncRNA regulates expression and function of innate immune transcription factor IRF1 in macrophages.

The discovery of long non-coding RNAs (lncRNAs) has provided a new perspective on the centrality of RNA in gene regulation and genome organization. Here, we screened for lncRNAs with putative functions in the host response to single-stranded RNA respiratory viruses. We identify as a conserved cis-acting lncRNA up-regulated in three respiratory diseases to control the expression of its antisense gene , a key transcriptional regulator of the antiviral response. and are coordinately increased in the circulation of patients infected with human metapneumovirus, influenza A virus, or SARS-CoV-2, and in macrophages in response to viral infection or TLR3 agonist treatment. Targeted depletion of or its mouse ortholog in macrophages reduces the expression of IRF1/Irf1 and their associated target gene networks, increasing susceptibility to viral infection. Accordingly, CRISPR-mediated deletion of in mice reduces antiviral immunity, increasing viral burden upon sublethal challenge with influenza A virus. Together, these findings identify a conserved role of lncRNA in coordinating interferon-stimulated genes and antiviral immune responses.