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Sphingosine Kinase Mediates Activation of Extracellular Signal–Related Kinase and Akt by Respiratory Syncytial Virus

University of Iowa Roy J. and Lucille A. Carver College of Medicine, and Veterans Administration Medical Center, Iowa City, Iowa

Address correspondence to: Martha M. Monick, Division of Pulmonary, Critical Care, and Occupational Medicine, Room 100, EMRB, University of Iowa Roy J. and Lucille A. Carver College of Medicine, Iowa City, IA 52242. E-mail: martha-monick{at}uiowa.edu

Respiratory syncytial virus (RSV) preferentially infects lung epithelial cells. Infected cells remain viable well into the infection. This prolonged survival results from RSV-induced activation of pro-survival pathways, including Akt and extracellular signal-related kinase (ERK). Sphingosine 1-phosphate (S1P) is a sphingolipid metabolite with demonstrated links to cell survival. It is enzymatically generated by sequential activation of ceramidase (generation of sphingosine) and sphingosine kinase (generation of S1P). In these studies, we found that RSV stimulated neutral ceramidase and sphingosine kinase activities in lung epithelial cells. The combined effect of activation of these two enzymes would decrease proapoptotic ceramide and increase antiapoptotic S1P. S1P activated Akt and ERK within minutes, and inhibition of sphingosine kinase blocked RSV-induced ERK and Akt activation, leading to accelerated cell death after viral infection. RSV infection does eventually kill infected cells but activation of cell survival pathways significantly delays cell death. The studies are the first evidence linking sphingolipid metabolites to cell survival mechanisms in the context of a viral infection.

Abbreviations: extracellular signal–related kinase, ERK • human tracheobronchial epithelial cells, hTBEs • polymerase chain reaction, PCR • phosphatidylinositol 3, PI 3 • respiratory syncytial virus, RSV • reverse transcriptase, RT • sphingosine 1-phosphate, S1P

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