# Regulation of RNA sensing and viral restriction by RNA structures

> **NIH NIH R01** · UNIVERSITY OF WASHINGTON · 2024 · $441,250

## Abstract

PROJECT SUMMARY
Venezuelan equine encephalitis virus (VEEV) is a single-stranded positive-sense RNA virus transmitted by
mosquitoes and is responsible for periodic epizootic/epidemic outbreaks of encephalitis in both horses and
humans. The innate and interferon (IFN) responses are critical barriers for preventing the replication and spread
of many viral pathogens including alphaviruses such as VEEV. As a result, viruses have evolved diverse
mechanisms to inhibit or escape the innate immune response as well as antiviral effectors such as IFN-stimulated
genes (ISGs). RNA structures are known to regulate basic viral processes (e.g. viral RNA transcription and
translation), however, the role that viral RNA structure plays in shaping innate immune responses to viruses is
understudied. We have previously shown that alphaviruses encode stable structures within their 5’-untranslated
region (5’-UTR) that are critical for antagonizing IFIT1, an ISG important in restriction of non-self RNA. We have
also shown that RNA structures in the 3’-UTR are important in modulating recognition of viral RNA by IFIT2.
Recently we have shown that RNA structures in the 3’-UTR and E1 modulate replication of virulent and avirulent
VEEV in macrophages, which are important targets of VEEV infection in vivo. The broad objectives of this
proposal are to: 1) delineate E1 RNA structural determinants in virulent and avirulent VEEV that regulate
macrophage replication, 2) define how E1 structural determinants recruit RBPs to the viral genome and the
impact of this on host innate immune responses, 3) Define how macrophage replication fitness contributes to
the differential pathogenesis in vivo of VEEV encoding virulent and avirulent RNA structures, and 4) Define how
macrophage replication fitness shapes innate immune responses in vivo. Findings from these studies will provide
key insight into novel mechanisms of VEEV pathogenesis and emergence of pathogenic variants. This will have
broad implications for our understanding of viral emergence and development of RNA-based therapeutics.

## Key facts

- **NIH application ID:** 10798244
- **Project number:** 5R01AI155416-02
- **Recipient organization:** UNIVERSITY OF WASHINGTON
- **Principal Investigator:** Jennifer Lynn Hyde
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2024
- **Award amount:** $441,250
- **Award type:** 5
- **Project period:** 2023-03-01 → 2028-02-29

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10798244

## Citation

> US National Institutes of Health, RePORTER application 10798244, Regulation of RNA sensing and viral restriction by RNA structures (5R01AI155416-02). Retrieved via AI Analytics 2026-06-12 from https://api.ai-analytics.org/grant/nih/10798244. Licensed CC0.

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