Acute respiratory tract infections are a leading cause of morbidity and mortality in children worldwide. Respiratory syncytial virus (RSV) is a major cause of lower respiratory tract infections in children, elderly and in immunocompromised patients, as well as of asthma exacerbations. No effective treatment or vaccine for RSV is currently available, and many fundamental questions regarding the pathogenesis of RSV-induced lung disease have yet to be answered. In the past project period, we pioneered work demonstrating the importance of oxidative injury in the pathogenesis of RSV infection, and the possible use of antioxidant intervention for this infection. Our new data provide novel mechanistic evidence in support of these findings, as we show that RSV infection results in downregulation of antioxidant enzyme (AOE) gene expression in human airway epithelial cells (hAECs), in mouse lung, and in children with bronchiolitis. Nuclear levels of NF- E2-related factor 2 (Nrf2), which regulates basal and inducible expression of AOE genes, are significantty decreased in response to RSV infection both in hAECs and in mouse lungs, while expression/activity of AOE negative transcriptional regulators is increased in response to RSV infection. The central hypothesis for our next grant period is that ROS production, along with the inhibition of cytoprotective AOE expression due to decreased Nrf2-dependent gene transcription, leads to clinical manifestations of RSV infection.
Aim 1 will test the hypothesis that antagonism between positive and negative transcriptional regulators determines the level of AOE gene expression in the context of viral infection.
Aim 2 will test the hypothesis that increased antioxidant cellular defenses decrease ROS production, oxidative stress and lung disease in response to RSV infection.
Aim 3 will test the hypothesis that decreased AOE gene expression is associated with greater severity of illness in infants with naturally acquired RSV infection. This project is synergistic with all the other projects of this Program Project, as it will include experiments linked to the fundamental scientific questions asked in PI. P3 and P4. related to the role of ROS-dependent activation of NF-KB (PI), formation of 8-oxo- guanine. which triggers novel GTPase-dependent cellular signaling (P3). and ROS-dependent signaling in response to allergen stimulation (P4). Completion of our studies will provide critical new information elucidating an important and novel molecular pathway by which respiratory viruses induce lung inflammation, with strong implications for developing novel therapeutic strategies ifor lower respiratory tract infections and virus-triggered precipitation of asthma attacks.

Public Health Relevance

; Respiratory syncytial virus (RSV) is a major cause of bronchiolitis, pneumonia and flu-like syndromes, as well as asthma attacks, and so represents a substantial public health problem for the community. 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, thereby reducing RSV-associated morbidity and mortality.

National Institute of Health (NIH)
National Institute of Allergy and Infectious Diseases (NIAID)
Research Program Projects (P01)
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Allergy & Clinical Immunology-1 (AITC)
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University of Texas Medical Br Galveston
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Bazhanov, Nikolay; Escaffre, Olivier; Freiberg, Alexander N et al. (2017) Broad-Range Antiviral Activity of Hydrogen Sulfide Against Highly Pathogenic RNA Viruses. Sci Rep 7:41029
Tian, Bing; Patrikeev, Igor; Ochoa, Lorenzo et al. (2017) NF-?B Mediates Mesenchymal Transition, Remodeling, and Pulmonary Fibrosis in Response to Chronic Inflammation by Viral RNA Patterns. Am J Respir Cell Mol Biol 56:506-520
Zhang, Yueqing; Sun, Hong; Zhang, Jing et al. (2017) Quantitative Assessment of the Effects of Trypsin Digestion Methods on Affinity Purification-Mass Spectrometry-based Protein-Protein Interaction Analysis. J Proteome Res 16:3068-3082
Agod, Zsofia; Fekete, T√ľnde; Budai, Marietta M et al. (2017) Regulation of type I interferon responses by mitochondria-derived reactive oxygen species in plasmacytoid dendritic cells. Redox Biol 13:633-645
Zhao, Yingxin; Jamaluddin, Mohammad; Zhang, Yueqing et al. (2017) Systematic Analysis of Cell-Type Differences in the Epithelial Secretome Reveals Insights into the Pathogenesis of Respiratory Syncytial Virus-Induced Lower Respiratory Tract Infections. J Immunol 198:3345-3364
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
German, Peter; Saenz, David; Szaniszlo, Peter et al. (2017) 8-Oxoguanine DNA glycosylase1-driven DNA repair-A paradoxical role in lung aging. Mech Ageing Dev 161:51-65
Tian, Bing; Yang, Jun; Zhao, Yingxin et al. (2017) BRD4 Couples NF-?B/RelA with Airway Inflammation and the IRF-RIG-I Amplification Loop in Respiratory Syncytial Virus Infection. J Virol 91:
Ke, Yueshuang; Han, Yanlong; Guo, Xiaolan et al. (2017) PARP1 promotes gene expression at the post-transcriptiona level by modulating the RNA-binding protein HuR. Nat Commun 8:14632
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

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