Hydrogen sulfide (H2S) is a novel gaseous mediator that has gained increasing recognition as an important intracellular modulator of cellular signaling, leading to increased anti-inflammatory and cytoprotective responses in models of acute and chronic inflammatory diseases. Paramyxoviruses, in particular, respiratory syncytial virus (RSV), are a major cause of upper and lower respiratory tract infections in children, elderly and immunocompromised hosts, for which no effective treatment or vaccine is currently available. Recent investigations in our laboratory uncovered a critical protective role of H2S in RSV infection, by modulating innate inflammatory responses and viral replication both in vitro and in vivo. Airway epithelial cells infected with RSV display decreased ability to generate H2S and enhanced degradation of H2S, indicating that viral infection leads to changes in H2S cellular homeostasis. Inhibition of H2S generation is associated with enhanced cytokine and chemokine production in vitro, and lack of cystathionine-?-lyase (CSE), one of the best characterized H2S-generating enzymes, results in increased disease severity in a mouse model of infection. Administration of H2S donors result in inhibition of activation of key transcription factors involved in viral- induced proinflammatory gene expression, by affecting their ability to drive gene transcription, but not their nuclear translocation, as well as, in amelioration of clinical disease in mice. In addition to its anti-inflammatory and antiviral activity, H2S administration also reduces viral-induced oxidative cell damage, which we have shown to play an important role in disease pathogenesis, supporting an important modulatory role of the cellular antioxidant pathway in the course of RSV infection. In this application, we will begin to identify the mechanism(s) by which H2S modulates viral-induced cellular signaling and start defining the contribution of H2S-generating enzymes other CSE in cellular antiviral and anti-inflammatory activity. Upon completion of the proposed investigations, we will obtain new critical information regarding the mechanisms of RSV-induced cellular signaling, which may allow us to specifically modulate viral-induced gene expression and therefore, antiviral and innate immune/inflammatory responses. Our results will help elucidate an important and novel molecular pathway by which respiratory viruses modulate lung disease, with strong implications for developing novel therapeutic strategies not only against RSV-induced lower respiratory tract infections (LRTI), but possibly against other important paramyxoviruses, responsible for severe human infections.

Public Health Relevance

Respiratory syncytial virus (RSV) is associated with bronchiolitis, pneumonia and flu-like syndromes, as well as asthma exacerbations, and it is considered a serious public health problem, for which no effective treatment or vaccine is currently available, while many fundamental questions regarding the pathogenesis of its associated lung disease still need to be answered. This project seeks to provide a greatly needed understanding of the molecular mechanisms that cause lung injury in RSV lower respiratory tract infections. Our results should lead to new pharmacologic strategies to prevent or treat these serious infections, therefore reducing RSV- associated morbidity and mortality.

Agency
National Institute of Health (NIH)
Institute
National Institute of Allergy and Infectious Diseases (NIAID)
Type
Exploratory/Developmental Grants (R21)
Project #
5R21AI122142-02
Application #
9391170
Study Section
Innate Immunity and Inflammation Study Section (III)
Program Officer
Kim, Sonnie
Project Start
2016-12-01
Project End
2018-11-30
Budget Start
2017-12-01
Budget End
2018-11-30
Support Year
2
Fiscal Year
2018
Total Cost
Indirect Cost
Name
University of Texas Med Br Galveston
Department
Pediatrics
Type
Schools of Medicine
DUNS #
800771149
City
Galveston
State
TX
Country
United States
Zip Code
77555
Komaravelli, Narayana; Ansar, Maria; Garofalo, Roberto P et al. (2017) Respiratory syncytial virus induces NRF2 degradation through a promyelocytic leukemia protein - ring finger protein 4 dependent pathway. Free Radic Biol Med 113:494-504
Bazhanov, Nikolay; Ansar, Maria; Ivanciuc, Teodora et al. (2017) Hydrogen Sulfide: A Novel Player in Airway Development, Pathophysiology of Respiratory Diseases, and Antiviral Defenses. Am J Respir Cell Mol Biol 57:403-410