Project 3 (Casola, A.)
Antonella Casola, MD
Associate 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...
The respiratory epithelium represents the principal cellular barrier between the environment and the internal milieu of the airways. Following inhalation of infectious agents, the epithelium is able to secrete a variety of molecules involved in inflammatory and immune responses, like cytokines and chemokines. Respiratory syncytial virus (RSV) is a potent stimulus of cytokines and chemokines gene expression in airway epithelial cells. We have shown that during the process of viral uncoating, transcription and viral replication, RSV induces several intracellular signals leading to activation of a subset of transcription factors, including NF-kB, AP-1, STAT and IRF, which are necessary for RSV-induced chemokine gene expression. Activation of NF-kB, STAT and IRF, following RSV infection, occurs through redox-sensitive pathways since it is inhibited by antioxidant treatment of airway epithelial cells. RSV infection is a strong inducer of reactive oxygen species (ROS), ubiquitous, highly diffusable and reactive molecules which function as important regulators of intracellular signaling. In this project, we are investigating the role of ROS in modulating intracellular protein phosphatase (PTP) activity, as well as in activation of IKKe, a recently cloned IKK-like kinase, as novel signaling pathways leading to STAT, IRF and NF-kB induction in airway epithelial cell, following RSV infection. Our major aims are:
- To investigate the role of ROS in protein tyrosine phosphatase activity and its relationship to RSV-induced STAT activation.
- To determine the role of ROS in RSV-induced IKKe activation.
- To identify ROS-dependent mechanisms regulating NF-kB driven transcription.
Insights gained from these studies will be instrumental in formulating novel therapeutic approaches for the treatment of viral-induced lung inflammation and post-infectious asthma.
- Casola A, Henderson A, Liu T, Garofalo RP and Brasier AR. Regulation of RANTES gene transcription following cytokine stimulation. Am J Physiol 2002; 283: L1280-90.
- Tian B, Zhang Y, Luxon BA, Garofalo RP, Casola A, Sinha M and Brasier AR. Identification of NF-?B dependent gene networks in respiratory syncytial virus-infected cells. J Virol 2002; 76: 6800-14.
- Zhang Y, Jamaluddin M, Wang S, Tian B, Garofalo RP, Casola A and Brasier AR. Ribavirin treatment upregulates antiviral gene expression via the interferon stimulated response element in RSV-infected epithelial cells. J Virol 2003; 77: 5933-47.
- Haeberle H, Casola A, Dieterich HJ, Brasier AR, Ernst PB, Gatalica Z and Garofalo RP. I?B kinase is a critical regulator of chemokine expression and lung inflammation in respiratory syncytial virus infection. J Virol 2004;78:2232-2241.
- Liu T, Castro S, Jamaluddin M, Brasier AR, Garofalo RP and Casola A. ROS mediate viral-induced stat activation: role of tyrosine phosphatases. J Biol Chem 2004; 279: 2461-2469.
- Yamaoka Y, Kudo T, Lu H, Brasier AR, Casola A and Graham DY. Role of the ISRE-like element in IL-8 promoter in H. pylori infection. Gastroenterology 2004; 126: 1030-43.
- Mogensen TH, Melchjorsen J, Malmgaard L, Casola A and Paludan SR. Suppression of proinflammatory cytokine expression by herpes symplex type I. J Virol 2004; 78: 5883-90.
- Brasier AR, Spratt H, Wu Z, Boldogh I, Zhang Y, Garofalo RP, Casola A, Pashmi J, Haag A, Luxon B and A Kurosky. Nuclear Heat Shock Response and Novel Nuclear Domain 10 Reorganization in Respiratory Syncytial Virus-Infected A549 Cells Identified By High Resolution 2D Gel Electrophoresis J Virol 2004, 78: 11461-11476.