Respiratory Syncytial Virus Decreases p53 Protein to Prolong Survival of Airway Epithelial Cells

Division of Pulmonary, Critical Care, and Occupational Medicine, Department of Pharmacology, University of Iowa Roy J. and Lucille A. Carver College of Medicine, Iowa City, IA 52242, USA.
The Journal of Immunology (Impact Factor: 4.92). 10/2007; 179(5):2741-7. DOI: 10.4049/jimmunol.179.5.2741
Source: PubMed


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.

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Available from: Linda S Powers, Oct 02, 2015
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    • "ELF4 has been shown to be induced in RSV-infected cells at 12 h p.i., leading to expression of the E3 ubiquitin ligase Mdm2, which ubiquitinates p53 and targets it for proteasome-mediated degradation (Maddika & Chen, 2009). As previous studies have shown that RSV infection arrests cells in G1 (Johnson et al., 2007; Mohapatra et al., 2009), our findings of let-7 inhibition of CCND1, DYRK2 and ELF4 translation suggest that let-7-mediated gene regulation is one of the mechanisms employed by RSV (Groskreutz et al., 2007; Mohapatra et al., 2009). "
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    ABSTRACT: Respiratory syncytial virus (RSV) causes substantial morbidity and life-threatening lower respiratory tract disease in infants, young children and the elderly. Understanding the host response to RSV infection is critical for developing disease-intervention approaches. The role of microRNAs (miRNAs) in post-transcriptional regulation of host genes responding to RSV infection is not well understood. In this study, it was shown that RSV infection of a human alveolar epithelial cell line (A549) induced five miRNAs (let-7f, miR-24, miR-337-3p, miR-26b and miR-520a-5p) and repressed two miRNAs (miR-198 and miR-595), and showed that RSV G protein triggered let-7f expression. Luciferase-untranslated region reporters and miRNA mimics and inhibitors validated the predicted targets, which included cell-cycle genes (CCND1, DYRK2 and ELF4), a chemokine gene (CCL7) and the suppressor of cytokine signalling 3 gene (SOCS3). Modulating let-7 family miRNA levels with miRNA mimics and inhibitors affected RSV replication, indicating that RSV modulates host miRNA expression to affect the outcome of the antiviral host response, and this was mediated in part through RSV G protein expression.
    Journal of General Virology 08/2012; 93(Pt 11):2346-56. DOI:10.1099/vir.0.044255-0 · 3.18 Impact Factor
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    • "These inhibitors can target either kinases in cellular pathways used by viruses, or alternatively viral kinases. Among the cellular kinases, the PI3K-Akt pathway is a prime candidate since it is affected by some viruses (Table 1), such as RSV [117], and there is a large number of inhibitors available or in development [136]. Regarding viral kinases, up to now only one the B1R kinase form poxviruses virus has been identified as affecting the pre pathway [72], thus development of specific inhibitors for this kinase is a challenge, since its eventual utilization includes viruses such as smallpox, which is a potential bioterrorist threat. "
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    ABSTRACT: Viral infections cause a major stress in host cells. The cellular responses to stress are mediated by p53, which by deregulation of cell cycle and apoptosis, may also be part of the host cell reaction to fight infections. Therefore, during evolutionary viral adaptation to host organisms, viruses have developed strategies to manipulate host cell p53 dependent pathways to facilitate their viral life cycles. Thus, interference with p53 function is an important component in viral pathogenesis. Many viruses have proteins that directly affect p53, whereas others alter the regulation of p53 in an indirect manner, mediated by Hdm2 or Akt, or induction of interferon. Rescue of p53 activity is becoming an area of therapeutic development in oncology. It might be feasible that manipulation of p53 mediated responses can become a therapeutic option to limit viral replication or dissemination. In this report, the mechanisms by which viral proteins manipulate p53 responses are reviewed, and it is proposed that a pharmacological rescue of p53 functions might help to control viral infections. Copyright © 2011 John Wiley & Sons, Ltd.
    Reviews in Medical Virology 06/2011; 21(5). DOI:10.1002/rmv.696 · 5.57 Impact Factor
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    • "In sharp contrast other viruses have evolved mechanisms to use p53 activity in its own benefit. Thus, p53 enhances the ability of human cytomegalovirus (HCMV) to replicate in fibroblasts [39], increases respiratory syncytial virus (RSV) [40] or adenovirus replication [41] and its absence has a detrimental effect in the growth of encephalomyocarditis virus (EMCV) and parainfluenza virus [38]. A possible explanation for this striking observation is that, while early apoptosis is probably detrimental for replication of some viruses, other viruses may benefit from apoptosis late in the replication cycle in order to improve transmission of newly-formed viral particles to other cells or hosts [42]. "
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    ABSTRACT: Tumor suppressor p53 is widely known as 'the guardian of the genome' due to its ability to prevent the emergence of transformed cells by the induction of cell cycle arrest and apoptosis. However, recent studies indicate that p53 is also a direct transcriptional target of type I interferons (IFNs) and thus, it is activated by these cytokines upon viral infection. p53 has been shown to contribute to virus-induced apoptosis, therefore dampening the ability of a wide range of viruses to replicate and spread. Interestingly, recent studies also indicate that several IFN-inducible genes such as interferon regulatory factor 9 (IRF9), IRF5, IFN-stimulated gene 15 (ISG15) and toll-like receptor 3 (TLR3) are in fact, p53 direct transcriptional targets. These findings indicate that p53 may play a key role in antiviral innate immunity by both inducing apoptosis in response to viral infection, and enforcing the type I IFN response, and provide a new insight into the evolutionary reasons why many viruses encode p53 antagonistic proteins.
    Viruses 01/2010; 2(1):298-313. DOI:10.3390/v2010298 · 3.35 Impact Factor
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