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* Division of Pulmonary, Critical Care, and Occupational Medicine,
Department of Pharmacology, and
Department of Microbiology and Interdisciplinary Graduate Program in Immunology, University of Iowa Roy J. and Lucille A. Carver College of Medicine and Veterans Administration Medical Center, Iowa City, IA 52242
Respiratory syncytial virus (RSV) is a clinically important pathogen. It preferentially infects airway epithelial cells causing bronchiolitis in infants, exacerbations in patients with obstructive lung disease, and life-threatening pneumonia in the immunosuppressed. The p53 protein is a tumor suppressor protein that promotes apoptosis and is tightly regulated for optimal cell growth and survival. A critical negative regulator of p53 is murine double minute 2 (Mdm2), an E3 ubiquitin ligase that targets p53 for proteasome degradation. Mdm2 is activated by phospho-Akt, and we previously showed that RSV activates Akt and delays apoptosis in primary human airway epithelial cells. In this study, we explore further the mechanism by which RSV regulates p53 to delay apoptosis but paradoxically enhance inflammation. We found that RSV activates Mdm2 1–6 h after infection resulting in a decrease in p53 6–24 h after infection. The p53 down-regulation correlates with increased airway epithelial cell longevity. Importantly, inhibition of the PI3K/Akt pathway blocks the activation of Mdm2 by RSV and preserves the p53 response. The effects of RSV infection are antagonized by Nutlin-3, a specific chemical inhibitor that prevents the Mdm2/p53 association. Nutlin-3 treatment increases endogenous p53 expression in RSV infected cells, causing earlier cell death. This same increase in p53 enhances viral replication and limits the inflammatory response as measured by IL-6 protein. These findings reveal that RSV decreases p53 by enhancing Akt/Mdm2-mediated p53 degradation, thereby delaying apoptosis and prolonging survival of airway epithelial cells.
The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked advertisement in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.
1 This work was supported by a Veterans Affairs Merit Review grant, by Grants HL-60316, HL-077431, and HL079901-01A1 from the National Institutes of Health, and by Grant RR00059 from the General Clinical Research Centers Program, National Center for Research Resources, National Institutes of Health.
2 Address correspondence and reprint requests Dr. Dayna Groskreutz, Division of Pulmonary, Critical Care, and Occupational Medicine, 100 Eckstein Medical Research Building, University of Iowa Roy J. and Lucille A. Carver College of Medicine, Iowa City, IA 52242. E-mail address: Dayna-Groskreutz{at}uiowa.edu
3 Abbreviations used in this paper: RSV, respiratory syncytial virus; MOI, multiplicity of infection; HTBE, human tracheobronchial epithelial; Mdm2, murine double minute 2.
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