Respiratory syncytial virus (RSV) is the most common cause of epidemic respiratory disease in children, responsible for 100,000 hospital admissions annually in the US alone, for which no vaccine or effective treatment is currently available. In the past years, we have shown that RSV infection leads to activation of the transcription factor Nuclear Factor (NF)-kB, as well as to the rapid generation of reactive oxygen species (ROS), both of which are involved in the expression of chemokines, proinflammatory mediators that regulate the migration and activation of leukocytes to the site of infection. In addition, RSV-induced ROS generation is associated with oxidative stress and lung damage both in vitro and in vivo, due to an imbalance between ROS production and antioxidant cellular defenses. Preliminary experiments revealed a new and fundamental role of NF-kB in modulating AOE gene expression in response to RSV infection, by inhibiting activation of NF-E2- related factor 2 (Nrf2), which regulates basal and inducible expression of AOE genes. In this project we will pursue the hypothesis that NF-?B plays a key role in RSV-induced lung disease as it antagonizes Nrf2- dependent gene expression, leading to inhibition of airway antioxidant defenses and subsequent oxidative lung damage. We will test our hypothesis by pursuing the following Specific Aims:
Aim 1. To determine the mechanism(s) by which NF-kB activation leads to inhibition of Nrf2 activation. We will investigate whether NF- kB affects Nrf2 activation by affecting its acetylation, through the recruitment of histone deacetylases and competition of transcriptional coactivators, and by promoting Nrf2 ubiquitination and degradation.
Aim 2. To investigate whether modulation of RSV-induced NF-kB activation in vivo leads to decreased lung oxidative stress and disease. We will pharmacologically inhibit NF-kB activation in a mouse model of RSV infection and assess markers of oxidative injury, AOE expression and clinical disease. Our results will help elucidate an important and novel molecular pathway by which respiratory viruses induce lung disease, with strong implications for developing novel therapeutic strategies not only against viral-induced lower respiratory tract infections (LRTI) but also other acute and chronic lung diseases where inflammation and oxidative stress play an important pathogenic role, such as asthma and chronic obstructive pulmonary disease.

Public Health Relevance

Acute respiratory tract infections are a leading cause of morbidity and mortality in children worldwide. Respiratory syncytial virus (RSV) is associated with bronchiolitis, pneumonia and flu-like syndrome, as well as asthma exacerbations, and it is considered a serious public health problem, yet no effective treatment or vaccine for RSV is currently available, and many fundamental questions regarding the pathogenesis of RSV- induced lung disease still need to be explored. This project seeks to provide a better understanding of the molecular mechanisms that cause lung injury in RSV lower respiratory tract infections and our results should lead to new pharmacologic strategies to prevent or treat these serious infections, therefore reducing RSV- associated complications.

National Institute of Health (NIH)
National Institute of Allergy and Infectious Diseases (NIAID)
Exploratory/Developmental Grants (R21)
Project #
Application #
Study Section
Special Emphasis Panel (ZRG1-IMM-N (03))
Program Officer
Kim, Sonnie
Project Start
Project End
Budget Start
Budget End
Support Year
Fiscal Year
Total Cost
Indirect Cost
University of Texas Medical Br Galveston
Schools of Medicine
United States
Zip Code
Ivanciuc, Teodora; Sbrana, Elena; Ansar, Maria et al. (2016) Hydrogen Sulfide Is an Antiviral and Antiinflammatory Endogenous Gasotransmitter in the Airways. Role in Respiratory Syncytial Virus Infection. Am J Respir Cell Mol Biol 55:684-696
Komaravelli, Narayana; Tian, Bing; Ivanciuc, Teodora et al. (2015) Respiratory syncytial virus infection down-regulates antioxidant enzyme expression by triggering deacetylation-proteasomal degradation of Nrf2. Free Radic Biol Med 88:391-403
Li, Hui; Ma, Yinghong; Escaffre, Oliver et al. (2015) Role of hydrogen sulfide in paramyxovirus infections. J Virol 89:5557-68
Komaravelli, Narayana; Casola, Antonella (2014) Respiratory Viral Infections and Subversion of Cellular Antioxidant Defenses. J Pharmacogenomics Pharmacoproteomics 5: