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Journal of Virology, April 2002, p. 3365-3373, Vol. 76, No. 7
0022-538X/02/$04.00+0     DOI: 10.1128/JVI.76.7.3365-3373.2002
Copyright © 2002, American Society for Microbiology. All Rights Reserved.

Coxsackievirus B3 Replication Is Reduced by Inhibition of the Extracellular Signal-Regulated Kinase (ERK) Signaling Pathway

Honglin Luo, Bobby Yanagawa, Jingchun Zhang, Zongshu Luo, Mary Zhang, Mitra Esfandiarei, Christopher Carthy, Janet E. Wilson, Decheng Yang, and Bruce M. McManus*

Department of Pathology and Laboratory Medicine, McDonald Research Laboratories/The iCAPTURE Center, St. Paul's Hospital/Providence Health Care-University of British Columbia, Vancouver, British Columbia, Canada

Received 27 August 2001/ Accepted 26 December 2001

Coxsackievirus B3 (CVB3) is the most common human pathogen for viral myocarditis. We have previously shown that the signaling protein p21ras GTPase-activating protein (RasGAP) is cleaved and that mitogen-activated protein kinases (MAPKs) ERK1/2 are activated in the late phase of CVB3 infection. However, the role of intracellular signaling pathways in CVB3-mediated myocarditis and the relative advantages of such pathways to host or virus remain largely unclear. In this study we extended our prior studies by examining the interaction between CVB3 replication and intracellular signaling pathways in HeLa cells. We observed that CVB3 infection induced a biphasic activation of ERK1/2, early transient activation versus late sustained activation, which were regulated by different mechanisms. Infection by UV-irradiated, inactivated virus capable of receptor binding and endocytosis triggered early ERK1/2 activation, but was insufficient to trigger late ERK1/2 activation. By using a general caspase inhibitor (zVAD.fmk) we further demonstrated that late ERK1/2 activation was not a result of CVB3-mediated caspase cleavage. Treatment of cells with U0126, a selective inhibitor of MAPK kinase (MEK), significantly inhibited CVB3 progeny release and decreased virus protein production. Furthermore, inhibition of ERK1/2 activation circumvented CVB3-induced apoptosis and viral protease-mediated RasGAP cleavage. Taken together, these data suggest that ERK1/2 activation is important for CVB3 replication and contributes to virus-mediated changes in host cells. Our findings demonstrate coxsackievirus takeover of a particular host signaling mechanism and uncover a prospective approach to stymie virus spread and preserve myocardial integrity.

* Corresponding author. Mailing address: Cardiovascular Research Laboratory, University of British Columbia-St. Paul's Hospital, 1081 Burrard St., Vancouver, British Columbia, Canada V6Z 1Y6. Phone: (604) 806-8586. Fax: (604) 806-8351. E-mail: bmcmanus{at}mrl.ubc.ca.

Journal of Virology, April 2002, p. 3365-3373, Vol. 76, No. 7
0022-538X/02/$04.00+0     DOI: 10.1128/JVI.76.7.3365-3373.2002
Copyright © 2002, American Society for Microbiology. All Rights Reserved.



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