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 ?-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 us ideally suited to pursue this innovative project.

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
Research Project (R01)
Project #
1R01AI125434-01A1
Application #
9311694
Study Section
Lung Cellular, Molecular, and Immunobiology Study Section (LCMI)
Program Officer
Kim, Sonnie
Project Start
2017-01-11
Project End
2021-12-31
Budget Start
2017-01-11
Budget End
2017-12-31
Support Year
1
Fiscal Year
2017
Total Cost
$503,750
Indirect Cost
$178,750
Name
University of Texas Medical Br Galveston
Department
Pediatrics
Type
Schools of Medicine
DUNS #
800771149
City
Galveston
State
TX
Country
United States
Zip Code
77555
Bazhanov, Nikolay; Ivanciuc, Teodora; Wu, Haotian et al. (2018) Thiol-Activated Hydrogen Sulfide Donors Antiviral and Anti-Inflammatory Activity in Respiratory Syncytial Virus Infection. Viruses 10:
Corsello, Tiziana; Komaravelli, Narayana; Casola, Antonella (2018) Role of Hydrogen Sulfide in NRF2- and Sirtuin-Dependent Maintenance of Cellular Redox Balance. Antioxidants (Basel) 7:
Ivanciuc, Teodora; Sbrana, Elena; Casola, Antonella et al. (2018) Protective Role of Nuclear Factor Erythroid 2-Related Factor 2 Against Respiratory Syncytial Virus and Human Metapneumovirus Infections. Front Immunol 9:854
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