# Hydrogen Sulfide and NRF2 Cross-talk in Viral Infections

> **NIH NIH R01** · UNIVERSITY OF TEXAS MED BR GALVESTON · 2021 · $503,750

## Abstract

PROJECT SUMMARY/ABSTRACT
Respiratory syncytial virus (RSV) is a major cause of upper and lower respiratory tract infections (LRTIs) in
children, elderly and immunocompromised hosts, for which no effective treatment or vaccine is available.
Children who develop RSV-induced bronchiolitis are also at increased risk for recurrent wheezing and
development of asthma in later life. Although the pathogenesis of RSV-induced disease remains a matter of
intense scientific debate, increasing evidence from experimental models and studies in naturally acquired
infections suggest that severe LRTIs are indeed associated with increased viral “load” and delayed viral
clearance due to an innate immune response that fails to restrict viral replication, yet causing inflammation and
tissue damage. The endogenously-generated gasotransmitter hydrogen sulfide (H2S) is implicated in a variety
of inflammatory and vascular disorders, associated with both pro- and anti-inflammatory signaling. Recently,
our group has gathered important new data, reagents and animals models that demonstrate a key role of H2S
in mediating antiviral and anti-inflammatory responses in the lung. In particular, we have shown that H2S
potently inhibits viral replication, exerts anti-inflammatory activity, and controls airway hyperresponsiveness in
RSV-infected mice. At the cellular level, we have shown that RSV is capable of inhibiting the expression of
cystathionine γ-lyase (CSE), the key enzyme that generates H2S is the lung, reducing the ability to generate
cellular H2S. We propose that dysregulation of the H2S pathway affects host antiviral response and plays a
critical role in the pathogenesis of severe RSV infections. Our findings indicate an important cross-talk between
H2S and the transcription factor NF-E2-related factor 2 (NRF2)-dependent pathways, which control the cellular
redox balance, each of them exerting a positive influence on the other, and both of them being downregulated
in the course of RSV infection. Thus, in this project, we will test the central hypothesis that inhibition of
cytoprotective H2S generation, due to decreased NRF2-dependent gene transcription, leads to clinical
manifestations of RSV infection. We will employ a combination of in vitro and in vivo approaches to test this
hypothesis, by the use of cells and mice genetically deficient in either NRF2 or H2S generating enzymes, and
the access to our ongoing cohort of infants and young children with primary RSV infections. This project will
elucidate innate pathways by which respiratory viruses modulate lung disease, with strong implications for
developing novel antiviral and anti-inflammatory therapeutic strategies for RSV-induced LRTI and possibly
long-term consequences, such as recurrent wheezing or asthma. Our long-standing clinical and research
expertise in the area of pathogenesis of viral bronchiolitis and RSV infections, strong preliminary data, and
UTMB's outstanding resources in the area of lung disease make ...

## Key facts

- **NIH application ID:** 9843442
- **Project number:** 5R01AI125434-04
- **Recipient organization:** UNIVERSITY OF TEXAS MED BR GALVESTON
- **Principal Investigator:** Antonella Casola
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2021
- **Award amount:** $503,750
- **Award type:** 5
- **Project period:** 2017-01-11 → 2022-12-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/9843442

## Citation

> US National Institutes of Health, RePORTER application 9843442, Hydrogen Sulfide and NRF2 Cross-talk in Viral Infections (5R01AI125434-04). Retrieved via AI Analytics 2026-05-23 from https://api.ai-analytics.org/grant/nih/9843442. Licensed CC0.

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