# Cellular RNAs in anti-viral immunity to HSV1 - Resubmission - 1

> **NIH NIH R21** · NEW YORK UNIVERSITY SCHOOL OF MEDICINE · 2021 · $148,752

## Abstract

Project Summary
Double-stranded RNA (dsRNA) is a potent pathogen-associated molecular pattern (PAMP) that activates cell
intrinsic antiviral defenses that inhibit protein synthesis and viral replication. Viral RNAs were previously regarded
as the primary ligands for cellular dsRNA sensors, however, cellular RNAs have recently been revealed to be
major regulators of nucleic acid PAMP responses capable of inhibiting and promoting their activation. Though
HSV1 is restricted by dsRNA-dependent antiviral effectors PKR and RNase L, what RNA activates these
enzymes and the contribution of newly characterized cellular calibrators of these responses is completely
unknown. Our overall objective is to understand how cellular RNAs contribute to antiviral immunity in
HSV1 infection. DsRNA-dependent responses are counteracted by several HSV1-encoded proteins,
underlining the importance of the task. These include vhs, an endoribonuclease which accelerates mRNA decay
minimizing dsRNA accumulation and Us11, which binds dsRNA preventing activation of the eIF2α kinase PKR
and RNase L. Our preliminary results indicate two opposing mechanisms exist by which cellular RNAs also
regulate dsRNA-dependent cell intrinsic defenses in HSV1 infected cells. First, we hypothesize that cellular
circular (circ) RNAs, protected from RNase L activation by Us11 and selectively preserved from vhs cleavage,
inhibit PKR activation. Second, we hypothesize that HSV1-induced dsRNA is not exclusively virus-encoded and
instead contains a cellular RNA component dependent on cytosolic DNA-sensing by cGAS-STING, the sensing
pathway that induces type I interferon (IFN) in response to HSV1. This would constitute a novel mode of signal
amplification and cross-talk between pathogenic DNA and RNA cytosolic detection systems. We will test these
hypotheses in two specific aims that (i) determine the role of circRNAs in HSV1 infection biology; and (ii) define
how the cGAS-STING dsDNA sensing pathway influences dsRNA abundance and/or antiviral dsRNA-dependent
innate immune responses. Completion of these specific aims will reveal how cell intrinsic innate immune
responses are regulated by host RNAs and parallel innate immune signaling pathways during infection with
HSV1, a medically important human pathogen. The results of this exploratory study are potentially applicable to
a wide variety of pathogenic human viruses and could reveal new strategies for treating virus infections. In
addition, they will provide important insights into cross-talk between innate immune signaling pathways involving
dsDNA and dsRNA that are important therapeutic targets for cancer and autoimmune disease.

## Key facts

- **NIH application ID:** 10218718
- **Project number:** 1R21AI151436-01A1
- **Recipient organization:** NEW YORK UNIVERSITY SCHOOL OF MEDICINE
- **Principal Investigator:** Hannah Marion Burgess
- **Activity code:** R21 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2021
- **Award amount:** $148,752
- **Award type:** 1
- **Project period:** 2021-08-19 → 2022-01-14

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10218718

## Citation

> US National Institutes of Health, RePORTER application 10218718, Cellular RNAs in anti-viral immunity to HSV1 - Resubmission - 1 (1R21AI151436-01A1). Retrieved via AI Analytics 2026-05-27 from https://api.ai-analytics.org/grant/nih/10218718. Licensed CC0.

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