Abstract 396: CHROMR Coordinates Interferon Signaling and Lipid Metabolism in Viral Infection

COVID-19, caused by SARS-CoV-2 infection, is associated with atherosclerotic cardiovascular complications like acute coronary syndrome, myocardial infarction, and stroke, but the underlying mechanisms are poorly understood. Long non-coding RNAs (lncRNAs) have emerged as important regulators of gene expression in the immune response. RNA-seq of whole blood from hospitalized patients with COVID-19, influenza A virus and matched controls identified 190 lncRNAs deregulated in both viral infections. Among the top mutually upregulated lncRNAs, we noted CHROMR (alias CHROME ) , a primate-specific lncRNA previously identified as a competing endogenous RNA that regulates cholesterol efflux and fatty acid oxidation via microRNA sequestration. Here, we report a complementary role for CHROMR in coordinating the interferon (IFN) signaling response to respiratory viruses. CHROMR expression is induced in macrophages in response to SARS-CoV-2 and influenza A infection and accumulates in the nucleus where it binds the transcriptional co-repressor IRF2BP2, a negative regulator of IFN-stimulated gene (ISG) expression. CHROMR is essential for mounting an anti-viral response, as its depletion in macrophages reduces histone acetylation at ISGs, activation of IRF signaling, and ISG expression. These findings suggest that CHROMR sequesters the nuclear IRF-2/IRF2BP2 repressor complex releasing its inhibitory effect on transcription of ISGs. Consistent with this, CHROMR expression is required to restrict influenza virus replication in macrophages. Notably, many viruses rewire host lipid synthesis and metabolism to facilitate replication, and thus, increased CHROMR expression in virus infected cells would both mitigate cellular lipid accumulation and increase ISG transcription to mount an anti-viral immune response. Collectively, our findings underscore the merit of investigating lncRNAs to decipher novel regulatory mechanisms that govern lipid metabolism and inflammation in humans.