Bronchiolitis & Asthma
The most recent report by the WHO estimates that about 3.5 million deaths occur every year worldwide from acute respiratory tract infections, of which 55% in children under the age of five. Bronchiolitis, one of the main clinical syndromes in hospitalized infants, accounts for up to 60% of all lower respiratory tract illnesses during the first year of life. Respiratory syncytial virus (RSV) is the single most important viral pathogen causing bronchiolitis in infants and children. Severe RSV infections have been linked to both the development and the severity of chronic asthma. Although premature infants and those with certain underlying medical conditions are predisposed to more severe infections, the majority of infants hospitalized because of serious RSV disease are born at term and otherwise healthy. The factors that contribute to the progression of upper respiratory tract infection to lower respiratory tract illness following RSV infection are not fully understood. In addition, it is currently unknown whether RSV or other viral respiratory pathogens are able to induce a chronic status of inflammation in the airways and how pathogen-specific respiratory infections affect host responses.
Dr. Garofalo has been in the forefront in dissecting a complex network of inflammatory and immunomodulatory genes of airway epithelium, in the role of airway cells in the orchestration of the inflammatory response in the lung, and in the relation of chemokines and pathogenesis of RSV infection and airway hyperreactivity (1-4). These critical observations have been translated to studies in infants and have provided a new paradigm in our understanding of the pathogenesis of respiratory viral infections and are going to be tested for the purpose of improving the diagnostic approach to viral LRTI (5-7). Examples of translational studies with potential for deliverables include those aimed to block airway inflammation, including the use of inhibitors of NF-?B (8) (9) and application of pharmacologic compounds that reduce the oxidative response (10), in association with novel anti-viral and vaccines strategies (11-13). These investigations are conducted in parallel with studies aimed to identify mucosal protein profiles and biomarkers that can be used to predict disease progression, clinical outcome or response to therapy.
- Saito, T., R. W. Deskin, A. Casola, H. Haeberle, B. Olszewska, P. B. Ernst, R. Alam, P. L. Ogra, and R. Garofalo. 1997. Respiratory syncytial virus induces selective production of the chemokine RANTES by upper airway epithelial cells. J Infect Dis 175:497-504.
- Olszewska-Pazdrak, B., A. Casola, T. Saito, R. Alam, S. E. Crowe, F. Mei, P. L. Ogra, and R. P. Garofalo. 1998. Cell-specific expression of RANTES, MCP-1, and MIP-1alpha by lower airway epithelial cells and eosinophils infected with respiratory syncytial virus. J Virol 72:4756-4764.
- Garofalo, R. P., F. Mei, R. Espejo, G. Ye, H. Haeberle, S. Baron, P. L. Ogra, and V. E. Reyes. 1997. Respiratory syncytial virus infection of human respiratory epithelial cells up-regulates class I MHC expression through the induction of IFN-b and IL-1a. J Immunol 157:2506-2513.
- Haeberle, H. A., W. A. Kuziel, H. J. Dieterich, A. Casola, Z. Gatalica, and R. P. Garofalo. 2001. Inducible expression of inflammatory chemokines in respiratory syncytial virus-infected mice: role of MIP-1alpha in lung pathology. J Virol 75:878-890.
- Garofalo, R. P., J. L. L. Kimpen, R. C. Welliver, and P. L. Ogra. 1992. Eosinophil degranulation in the respiratory tract during naturally acquired respiratory syncytial virus infection. J.Pediatrics 120:28-32.
- Garofalo, R. P., B. Olszewska-Pazdrak, P. L. Ogra, and R. C. Welliver. 2001. Beta-chemokines in nasal secretion of infants with respiratory syncytial virus-induced upper respiratory illness and bronchiolitis. Pediatric Asthma Allergy and Immunology 15:89-96.
- Garofalo, R. P. and H. Haeberle. 2000. Epithelial regulation of innate immunity to respiratory syncytial virus. Am J Respir Cell Mol Biol 23:581-585.
- Haeberle, H. A., A. Casola, Z. Gatalica, S. Petronella, H. J. Dieterich, P. B. Ernst, A. R. Brasier, and R. P. Garofalo. 2004. IkappaB Kinase Is a Critical Regulator of Chemokine Expression and Lung Inflammation in Respiratory Syncytial Virus Infection. J.Virol. 78:2232-2241.
- Haeberle, H. A., F. Nesti, H. J. Dieterich, Z. Gatalica, and R. P. Garofalo. 2002. Perflubron Reduces Lung Inflammation in Respiratory Syncytial Virus Infection by Inhibiting Chemokine Expression and Nuclear Factor-kappaB Activation. Am.J.Respir.Crit Care Med. 165:1433-1438.
- Liu, T., S. Castro, A. R. Brasier, M. Jamaluddin, R. P. Garofalo, and A. Casola. 2003. ROS mediate viral-induced stat activation: role of tyrosine phosphatases. J.Biol.Chem.
- Zhang, Y., M. Jamaluddin, S. Wang, B. Tian, R. P. Garofalo, A. Casola, and A. R. Brasier. 2003. Ribavirin treatment up-regulates antiviral gene expression via the interferon-stimulated response element in respiratory syncytial virus-infected epithelial cells. J Virol 77:5933-5947.
- Guerrero-Plata, A., S. Baron, J. S. Poast, P. A. Adegboyega, A. Casola, and R. P. Garofalo. 2005. Activity and regulation of alpha interferon in respiratory syncytial virus and human metapneumovirus experimental infections. J Virol 79:10190-10199.
- Liu, T., W. Zaman, B. S. Kaphalia, G. A. Ansari, R. P. Garofalo, and A. Casola. 2005. RSV-induced prostaglandin E2 production occurs via cPLA2 activation: role in viral replication. Virology 343:12-24.