Respiratory Syncytial Virus (RSV) is a leading cause of childhood respiratory disease, responsible for 75,000? 125,000 hospitalizations annually and producing significant morbidity and economic impact. No vaccine is currently licensed to prevent RSV infections. Children hospitalized for RSV lower respiratory tract infections (LRTIs) have reduced pulmonary function, a significant predictor of adult chronic lung disease. This is a competing renewal for our P01, originally funded as AADCRC AI46004 and subsequently through two P01 cycles (9/1/2005-present). Work in our P01 has elucidated mechanisms by which RSV infection produces a rapid epithelial oxidative stress response, triggering innate signaling and resulting in cytokine secretion that triggers and shapes adaptive immunity. More recently, we have developed additional compelling evidence supporting the central theme of this P01 ? that innate inflammation produced by infection with the ubiquitous viral pathogen RSV impairs antioxidant capacity, producing disease and triggering long-term airway remodeling. Our projects are developed from original discoveries by our internationally recognized project leaders (PLs) expert in innate inflammation, oxidative stress, and the DNA damage response. Our renewal includes three major research projects (RPs): 1) RP1 (?Epigenetic regulation of innate inflammation-driven airway remodeling?) will focus on the role of the NF?B-coactivator, a chromatin remodeling complex (CRC) nucleated by bromodomain-containing protein 4 (BRD4) in RSV-induced remodeling via epithelial- mesenchymal transition and myofibroblast expansion; 2) RP2 (?The role of innate immunity in downregulation of the airway antioxidant response during paramyxovirus infection?) will focus on how RSV causes disease mediated by unbalanced ROS production via a progressive decrease in NF-E2-related factor 2 (NRF2); and 3) RP3 (?Linkage of the oxidant induced OGG1-DNA complex to airway inflammation and remodeling?) will test the hypothesis that RSV-induced epigenetic modification via oxidation of guanine to oxoG in gene regulatory regions controls acute/chronic inflammation and airway remodeling via the NF?B pathway. This P01 is guided by regular and sustained interactions with our Internal and External Advisory Committees and is nurtured by significant institutional support from UTMB Centers, Departments, and Institutes. All our inter-related and synergistic RPs are supported by an Administrative Core, and human subjects and viral preparations from the Infant Bronchiolitis and Viral Core (IBVC). Translational advances include applications of BRD4 inhibitors, NRF2 agonists, and OGG1 inhibitors that in preclinical studies show promise to interfere with RSV-induced inflammation and remodeling. Upon completion, this P01 will have identified mechanisms of innate signaling-induced remodeling and developed strategies for reversing remodeling and restoring defective innate immunity in allergic airway diseases.

Public Health Relevance

Respiratory Syncytial Virus (RSV) is the major cause of pediatric lung infections worldwide, resulting in significant long-term consequences, including reductions in lung function and chronic respiratory disease later in life. This program grant examines how RSV infections reduce cellular protection to oxidative stress and modify the genome to trigger structural remodeling of the airway. We will provide proof-of-principle for treatments to counteract these damaging effects.

Agency
National Institute of Health (NIH)
Institute
National Institute of Allergy and Infectious Diseases (NIAID)
Type
Research Program Projects (P01)
Project #
2P01AI062885-11
Application #
9573990
Study Section
Special Emphasis Panel (ZAI1)
Program Officer
Davidson, Wendy F
Project Start
2004-09-01
Project End
2023-06-30
Budget Start
2018-07-25
Budget End
2019-06-30
Support Year
11
Fiscal Year
2018
Total Cost
Indirect Cost
Name
University of Texas Med Br Galveston
Department
Pediatrics
Type
Schools of Medicine
DUNS #
800771149
City
Galveston
State
TX
Country
United States
Zip Code
77555
Tian, Bing; Liu, Zhiqing; Yang, Jun et al. (2018) Selective Antagonists of the Bronchiolar Epithelial NF-?B-Bromodomain-Containing Protein 4 Pathway in Viral-Induced Airway Inflammation. Cell Rep 23:1138-1151
Ba, Xueqing; Boldogh, Istvan (2018) 8-Oxoguanine DNA glycosylase 1: Beyond repair of the oxidatively modified base lesions. Redox Biol 14:669-678
Visnes, Torkild; Cázares-Körner, Armando; Hao, Wenjing et al. (2018) Small-molecule inhibitor of OGG1 suppresses proinflammatory gene expression and inflammation. Science 362:834-839
Ochoa, Lorenzo F; Kholodnykh, Alexander; Villarreal, Paula et al. (2018) Imaging of Murine Whole Lung Fibrosis by Large Scale 3D Microscopy aided by Tissue Optical Clearing. Sci Rep 8:13348
Liu, Zhiqing; Tian, Bing; Chen, Haiying et al. (2018) Discovery of potent and selective BRD4 inhibitors capable of blocking TLR3-induced acute airway inflammation. Eur J Med Chem 151:450-461
Bao, Xiaoyong; Kolli, Deepthi; Esham, Dana et al. (2018) Human Metapneumovirus Small Hydrophobic Protein Inhibits Interferon Induction in Plasmacytoid Dendritic Cells. Viruses 10:
Chahar, Harendra Singh; Corsello, Tiziana; Kudlicki, Andrzej S et al. (2018) Respiratory Syncytial Virus Infection Changes Cargo Composition of Exosome Released from Airway Epithelial Cells. Sci Rep 8:387
Hosoki, Koa; Rajarathnam, Krishna; Sur, Sanjiv (2018) Attenuation of murine allergic airway inflammation with a CXCR1/CXCR2 chemokine receptor inhibitor. Clin Exp Allergy :
Tian, Bing; Widen, Steven G; Yang, Jun et al. (2018) The NF?B subunit RELA is a master transcriptional regulator of the committed epithelial-mesenchymal transition in airway epithelial cells. J Biol Chem 293:16528-16545
Graber, Ted G; Rawls, Brandy L; Tian, Bing et al. (2018) Repetitive TLR3 activation in the lung induces skeletal muscle adaptations and cachexia. Exp Gerontol 106:88-100

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