# Novel Role for Host Immunostimulatory RNA in Antiviral Immune Defense

> **NIH NIH R01** · CLEVELAND CLINIC LERNER COM-CWRU · 2021 · $450,805

## Abstract

PROJECT SUMMARY
Work from many laboratories has established that DNA sensors – both membrane-localized
Toll-like receptors (e.g. TLR9) and intracellular DNA sensors (e.g. cGAS) – sense herpesvirus
infection. In striking contrast, our knowledge about the physiologic relevance of cytoplasmic
RNA sensors of the RIG-I-like receptor (RLR) family in the detection of herpesviruses, such as
herpes simplex virus type 1 (HSV-1), is rudimentary.
The proposed study builds on a recent discovery by the Gack laboratory that RIG-I plays a
crucial role in the detection and restriction of HSV-1 infection, where RIG-I and intracellular DNA
sensors act in a temporal manner. Furthermore, we identified that during HSV-1 infection the
host-derived 5S ribosomal RNA pseudogene transcript 141 (RNA5SP141) activates RIG-I and
elicits cytokine-mediated antiviral innate immune defense. In collaborative work we recently
identified that ablated RNA5SP141 gene expression is associated with severe HSV-1
encephalitis in humans. Furthermore, we discovered that RNA5SP141 is exported from infected
cells via exosomes and taken up by uninfected cells, where it triggered RIG-I signaling.
Using a coordinated series of molecular, biochemical, and cell biological approaches combined
with CRISPR-gene editing techniques, we will define the role of RNA5SP141 gene expression
in the antiviral innate immune response to HSV-1 infection and in HSV-1-associated disease
(AIM 1). Furthermore, we will elucidate the molecular mechanism(s) underlying RNA5SP141
exosomal loading (AIM 2), and also determine the physiologic relevance of exosomal delivery of
RNA5SP141 in host immunity to HSV-1 infection (AIM 3). Our studies will provide a molecular
understanding of innate immune detection of herpesvirus infection, which may provide the
foundation for new therapeutic approaches or guide the design of novel adjuvants.

## Key facts

- **NIH application ID:** 10338487
- **Project number:** 1R01AI165502-01
- **Recipient organization:** CLEVELAND CLINIC LERNER COM-CWRU
- **Principal Investigator:** Michaela Ulrike Gack
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2021
- **Award amount:** $450,805
- **Award type:** 1
- **Project period:** 2021-09-22 → 2026-08-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10338487

## Citation

> US National Institutes of Health, RePORTER application 10338487, Novel Role for Host Immunostimulatory RNA in Antiviral Immune Defense (1R01AI165502-01). Retrieved via AI Analytics 2026-05-23 from https://api.ai-analytics.org/grant/nih/10338487. Licensed CC0.

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