Project 2 (Casola, A)
Antonella Casola, MD
Professor in Pediatrics
Pediatric Child Research Center
2.364 Children's Hospital
Department of Pediatrics
301 University Blvd.
Galveston, TX 77555-0366
Dr. Casola's bio...
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 few years, 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 most recent data indicate 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 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 project 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. Our aims are to:
The results obtained from these studies will help elucidate an important and novel molecular pathway by which respiratory viruses induce lung inflammation, and should lay the foundation for future studies to develop novel therapeutic strategies against lower respiratory tract infections and virus-triggered precipitation of asthma attacks.
- The antagonism between positive and negative transcriptional regulators determines the level of AOE gene expression in response to RSV infection
- Increased antioxidant cellular defenses decrease viral-associated ROS production, oxidative stress and lung disease
- Decreased AOE gene expression is associated with greater severity of illness in infants with naturally acquired RSV infection
- Bao, X., Liu, T., Shan, Y.C., Li, K., Garofalo, R.P, Casola, A. (2008). Human metapneumovirus glycoprotein G inhibits innate immune responses. PloS Pathog, 4:e1000077. PMCID: PMC 2386556
- Hosakote, Y.M., Liu, T., Castro, S.M., Garofalo, R.P., Casola, A. (2009). Respiratory syncytial virus induces oxidative stress by modulating antioxidant enzymes. Am J Respir Cell Mol Bio, 41:348-357. PMCID: PMC2742754
- Hosakote, Y.M., Jantzi, P., Esham, D., Kurosky, A., Casola, A. and Garofalo, R.P. (2011). Viral-mediated inhibition of antioxidant enzymes contributes to the pathogenesis of severe RSV bronchiolitis. Am J Resp Critic Care Med,183:1550-60. PMCID:PMC3137144
- Hosakote, Y.M., Komaravelli, N., Mautemps, N., Liu, T., Garofalo, R.P., and Casola, A. (2012). Antioxidant mimetics modulate oxidative stress and cellular signaling in airway epithelial cells infected with respiratory syncytial virus. Am J Physiol Lung Cell Mol Physiol, 303:L991-1000. PMCID:PMC3532525
- Kolli D, Bao X, Liu T, Hong C, Garofalo R.P., and Casola, A. (2011). Human metapneumovirus glycoprotein G modulates Toll-like receptor-4 signaling in monocyte-derived dendritic cells. J Immunol, 2011;187:47-54. PMCID: PMC3119724
- Dey N, Liu T, Garofalo RP and Casola A. (2011). TAK1 regulates NF-kB and AP-1 activation in airway epithelial cells following RSV infection. Virology, 418:93-101.
- Kolli D, Bao X and Casola A. (2012). Human metapneumovirus antagonisms of innate immune responses. Viruses, 4:3551-71.
- Bao X, Kolli D, Liu T, Garofalo R.P and Casola A. (2013). Human Metapneumovirus Glycoprotein G Disrupts Mitochondrial Signaling in Airway Epithelial Cells. PLoS One, 8:e62568
- Kolli D Y, Garofalo RP and Casola A. (2012). Respiratory Syncytial Virus (RSV) Infection: Mechanisms of Redox Control and Novel Therapeutic Opportunities. Comprehensive Invited Review (CIR) in Antioxidants & Redox Signaling,18:186-217.