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 NFE2- related factor 2 (Nrf2), which regulates basal and inducible expression of AOE genes, are significantly 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 P I . P3 and P4. related to the role of ROS-dependent activation of NF-KB (PI), formation of 8-oxoguanine. 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.

Agency
National Institute of Health (NIH)
Institute
National Institute of Allergy and Infectious Diseases (NIAID)
Type
Research Program Projects (P01)
Project #
5P01AI062885-07
Application #
8707683
Study Section
Allergy & Clinical Immunology-1 (AITC)
Project Start
Project End
Budget Start
2013-09-01
Budget End
2014-08-31
Support Year
7
Fiscal Year
2013
Total Cost
$431,957
Indirect Cost
$149,484
Name
University of Texas Medical Br Galveston
Department
Type
DUNS #
800771149
City
Galveston
State
TX
Country
United States
Zip Code
77555
Belanger, KarryAnne K; Ameredes, Bill T; Boldogh, Istvan et al. (2016) The Potential Role of 8-Oxoguanine DNA Glycosylase-Driven DNA Base Excision Repair in Exercise-Induced Asthma. Mediators Inflamm 2016:3762561
Hosoki, Koa; Itazawa, Toshiko; Boldogh, Istvan et al. (2016) Neutrophil recruitment by allergens contribute to allergic sensitization and allergic inflammation. Curr Opin Allergy Clin Immunol 16:45-50
Choudhary, Sanjeev; Boldogh, Istvan; Brasier, Allan R (2016) Inside-Out Signaling Pathways from Nuclear Reactive Oxygen Species Control Pulmonary Innate Immunity. J Innate Immun 8:143-55
Nicholson, Erin G; Schlegel, Chelsea; Garofalo, Roberto P et al. (2016) Robust Cytokine and Chemokine Response in Nasopharyngeal Secretions: Association With Decreased Severity in Children With Physician Diagnosed Bronchiolitis. J Infect Dis 214:649-55
German, Peter; Saenz, David; Szaniszlo, Peter et al. (2016) 8-Oxoguanine DNA glycosylase1-driven DNA repair-A paradoxical role in lung aging. Mech Ageing Dev :
Hosoki, Koa; Aguilera-Aguirre, Leopoldo; Brasier, Allan R et al. (2016) Facilitation of Allergic Sensitization and Allergic Airway Inflammation by Pollen-Induced Innate Neutrophil Recruitment. Am J Respir Cell Mol Biol 54:81-90
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
Bacsi, Attila; Pan, Lang; Ba, Xueqing et al. (2016) Pathophysiology of bronchoconstriction: role of oxidatively damaged DNA repair. Curr Opin Allergy Clin Immunol 16:59-67
Chakraborty, Anirban; Tapryal, Nisha; Venkova, Tatiana et al. (2016) Classical non-homologous end-joining pathway utilizes nascent RNA for error-free double-strand break repair of transcribed genes. Nat Commun 7:13049
Hosoki, Koa; Boldogh, Istvan; Aguilera-Aguirre, Leopoldo et al. (2016) Myeloid differentiation protein 2 facilitates pollen- and cat dander-induced innate and allergic airway inflammation. J Allergy Clin Immunol 137:1506-1513.e2

Showing the most recent 10 out of 126 publications