Type I IFNs control the expression of hundreds of interferon stimulated genes that collectively render infected and neighboring cells resistant to virus infection. While protein coding ISGs have been studied extensively, the role of non- coding RNAs as ISGs is only beginning to be appreciated. The discovery of long non-coding RNAs (lncRNAs) has provided a new perspective on gene regulation in the immune system. Only 2% of the mammalian genome contains genes that are translated into proteins. Yet, the vast majority of the genome is transcribed as RNA and lncRNAs account for most of these transcripts. lncRNAs are versatile molecules that interact with RNA, DNA, or proteins to positively or negatively regulate the expression of protein-coding genes. Emerging evidence from our lab and others, indicates that lncRNAs are regulated during anti-viral responses downstream of the IFN pathway. The function of most of these lncRNAs is unknown. We have used RNA-sequencing to understand the transcriptional response of both human and murine myeloid cells to multiple viruses including Influenza virus, Herpes simplex virus, Sendai virus and Dengue virus. We have identified lncRNAs that are regulated by multiple viruses as well as lncRNAs regulated in a virus-specific manner. We have begun to explore the immunobiology of these molecules in the context of host-virus interactions. We have also identified important cross talk between lincRNAs and immunometabolites of the TCA cycle. Itaconate is a citrate-derived intermediate of the TCA cycle that has anti-inflammatory activity. Itaconate shuts down both IL-1 and type I IFN responses to curb inflammation. The studies proposed in this application will define how metabolic pathways that are altered in virus infected cells couple to anti-viral immunity through lncRNAs. This proposal will focus on a lincRNA, LUCAT-1 that is itself an ISG. Intriguingly, LUCAT-1 is an itaconate regulated gene. In preliminary studies we have found that LUCAT-1 restrains the type I IFN response. Based on these findings we hypothesize that during virus infection itaconate production in virus infected cells leads to induction of LUCAT-1 expression in order to shut down the IFN response. We propose to study the regulation and function of the itaconate-LUCAT-1 axis during virus infection and determine the role of LUCAT-1 in coordinating the anti-inflammatory effects of itaconate on the ISG response and the impact of this pathway on anti-viral immunity. Collectively, these studies will shed new light on how metabolic rewiring in virus infected cells engage lncRNAs such as LUCAT-1 to restrain inflammatory responses.
The major class of RNA molecules produced from the genome are called long noncoding RNA (lncRNA), which appear to regulate the expression of other protein coding genes. The studies proposed in this application focus on how lncRNAs control the production of proteins that help block virus infection. Our lab has identified important lncRNAs that regulate anti-viral responses. We are proposing to study one of these lncRNAs and how it helps to turn off important anti-viral responses. We also propose to study how these lncRNAs are changed when the metabolism of the virus infected cell is rewired.
