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Journal of Virology, February 2007, p. 1230-1240, Vol. 81, No. 3
0022-538X/07/$08.00+0     doi:10.1128/JVI.01586-06
Copyright © 2007, American Society for Microbiology. All Rights Reserved.

The ERK Mitogen-Activated Protein Kinase Pathway Contributes to Ebola Virus Glycoprotein-Induced Cytotoxicity{triangledown}

Carisa A. Zampieri,1 Jean-Francois Fortin,2,{dagger} Garry P. Nolan,2 and Gary J. Nabel1*

Vaccine Research Center, NIAID, National Institutes of Health, Room 4502, Bldg. 40, MSC-3005, 40 Convent Drive, Bethesda, Maryland 20892-3005,1 Baxter Laboratory of Genetic Pharmacology, Dept. of Microbiology and Immunology, Stanford University School of Medicine, 269 Campus Drive, CCSR, Rm. 3205, Stanford, California 94305-51752

Received 24 July 2006/ Accepted 6 November 2006

Ebola virus is a highly lethal pathogen that causes hemorrhagic fever in humans and nonhuman primates. Among the seven known viral gene products, the envelope glycoprotein (GP) alone induces cell rounding and detachment that ultimately leads to cell death. Cellular cytoxicity is not seen with comparable levels of expression of a mutant form of GP lacking a mucin-like domain (GP{Delta}muc). GP-induced cell death is nonapoptotic and is preceded by downmodulation of cell surface molecules involved in signaling pathways, including certain integrins and epidermal growth factor receptor. To investigate the mechanism of GP-induced cellular toxicity, we analyzed the activation of several signal transduction pathways involved in cell growth and survival. The active form of extracellular signal-regulated kinases types 1 and 2 (ERK1/2), phospho-ERK1/2, was reduced in cells expressing GP compared to those expressing GP{Delta}muc as determined by flow cytometry, in contrast to the case for several other signaling proteins. Subsequent analysis of the activation states and kinase activities of related kinases revealed a more pronounced effect on the ERK2 kinase isoform. Disruption of ERK2 activity by a dominant negative ERK or by small interfering RNA-mediated ERK2 knockdown potentiated the decrease in {alpha}V integrin expression associated with toxicity. Conversely, activation of the pathway through the expression of a constitutively active form of ERK2 significantly protected against this effect. These results indicate that the ERK signaling cascade mediates GP-mediated cytotoxicity and plays a role in pathogenicity induced by this gene product.

* Corresponding author. Mailing address: Vaccine Research Center, NIAID, National Institutes of Health, Room 4502, Bldg. 40, MSC-3005, 40 Convent Drive, Bethesda, MD 20892-3005. Phone: (301) 496-1852. Fax: (301) 480-0274. E-mail: gnabel{at}nih.gov.

{triangledown} Published ahead of print on 15 November 2006.

{dagger} Present address: Research and Development, Boehringer Ingelheim (Canada) Ltd., 2100, Cunard St., Laval, Québec, Canada H7S 2G5.

Journal of Virology, February 2007, p. 1230-1240, Vol. 81, No. 3
0022-538X/07/$08.00+0     doi:10.1128/JVI.01586-06
Copyright © 2007, American Society for Microbiology. All Rights Reserved.



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