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
Brasier, Allan R (2014) Application of translational science to the clinical problem of asthma. Preface. Adv Exp Med Biol 795:v - vii
Bertolusso, Roberto; Tian, Bing; Zhao, Yingxin et al. (2014) Dynamic cross talk model of the epithelial innate immune response to double-stranded RNA stimulation: coordinated dynamics emerging from cell-level noise. PLoS One 9:e93396
Luo, Jixian; Hosoki, Koa; Bacsi, Attila et al. (2014) 8-Oxoguanine DNA glycosylase-1-mediated DNA repair is associated with Rho GTPase activation and ?-smooth muscle actin polymerization. Free Radic Biol Med 73:430-8
Ba, Xueqing; Aguilera-Aguirre, Leopoldo; Rashid, Qura Tul Ain Nmi et al. (2014) The role of 8-oxoguanine DNA glycosylase-1 in inflammation. Int J Mol Sci 15:16975-97
Aguilera-Aguirre, Leopoldo; Bacsi, Attila; Radak, Zsolt et al. (2014) Innate inflammation induced by the 8-oxoguanine DNA glycosylase-1-KRAS-NF-?B pathway. J Immunol 193:4643-53
Li, Xueling; Zhao, Yingxin; Tian, Bing et al. (2014) Modulation of gene expression regulated by the transcription factor NF-?B/RelA. J Biol Chem 289:11927-44
Ba, Xueqing; Bacsi, Attila; Luo, Jixian et al. (2014) 8-oxoguanine DNA glycosylase-1 augments proinflammatory gene expression by facilitating the recruitment of site-specific transcription factors. J Immunol 192:2384-94
Fang, Ling; Choudhary, Sanjeev; Zhao, Yingxin et al. (2014) ATM regulates NF-?B-dependent immediate-early genes via RelA Ser 276 phosphorylation coupled to CDK9 promoter recruitment. Nucleic Acids Res 42:8416-32
Ijaz, Talha; Pazdrak, Konrad; Kalita, Mridul et al. (2014) Systems biology approaches to understanding Epithelial Mesenchymal Transition (EMT) in mucosal remodeling and signaling in asthma. World Allergy Organ J 7:13
Kolli, Deepthi; Gupta, Meera R; Sbrana, Elena et al. (2014) Alveolar macrophages contribute to the pathogenesis of human metapneumovirus infection while protecting against respiratory syncytial virus infection. Am J Respir Cell Mol Biol 51:502-15

Showing the most recent 10 out of 82 publications