# Inc'ing RNA to anti-viral defense

> **NIH NIH R21** · UNIV OF MASSACHUSETTS MED SCH WORCESTER · 2020 · $209,375

## Abstract

Abstract
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.

## Key facts

- **NIH application ID:** 9948568
- **Project number:** 5R21AI147208-02
- **Recipient organization:** UNIV OF MASSACHUSETTS MED SCH WORCESTER
- **Principal Investigator:** Katherine A. Fitzgerald
- **Activity code:** R21 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2020
- **Award amount:** $209,375
- **Award type:** 5
- **Project period:** 2019-06-07 → 2021-05-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/9948568

## Citation

> US National Institutes of Health, RePORTER application 9948568, Inc'ing RNA to anti-viral defense (5R21AI147208-02). Retrieved via AI Analytics 2026-05-22 from https://api.ai-analytics.org/grant/nih/9948568. Licensed CC0.

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