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Am J Physiol Heart Circ Physiol 293: H69-H76, 2007. First published April 13, 2007; doi:10.1152/ajpheart.00154.2007
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TRANSLATIONAL PHYSIOLOGY

Antiviral and myocyte protective effects of murine interferon-beta and -{alpha}2 in coxsackievirus B3-induced myocarditis and epicarditis in Balb/c mice

Yi-Xin Wang,1 Valdeci da Cunha,1 Jon Vincelette,1 Kathy White,1 Sharlene Velichko,1 Yifan Xu,1 Cynthia Gross,1 Richard M. Fitch,1 Meredith Halks-Miller,1 Brent R. Larsen,1 Toshitaka Yajima,2 Kirk U. Knowlton,2 Ronald Vergona,1 Mark E. Sullivan,1 and Ed Croze1

1Berlex Biosciences, Richmond, California; and 2Department of Medicine, University of California, San Diego, California

Submitted 6 February 2007 ; accepted in final form 9 April 2007

The present study tested the hypothesis that murine (m)IFN-beta or mIFN-{alpha}2 can eliminate cardiac viral load and protect cardiomyocytes from injury in animals infected with coxsackievirus B3 (CVB3). CVB3-inoculated male Balb/c mice exhibited signs of illness, including lethargy, progressive weight loss, and death (10% on day 3 and 100% on day 8). Cardiac viral load was high [4,277 ± 1,009 plaque-forming units and 25 ± 5 copies CVB3/hypoxanthine guanine phosphoribosyl transferase 1 mRNA] on day 4. The cardiac tissue exhibited severe inflammatory infiltration and myocyte damage with an average myocarditis integrated pathology score of 2.1 ± 0.2 on day 7. Most of the mice infected with CVB3 also developed epicarditis, and 55% had intraventricular thrombi present. Treatment with mIFN-beta [2.5 to 10 million international units (MIU)/kg] dose-dependently improved the general health status in CVB3-inoculated mice, as evidenced by reduction in weight loss, prevention of death, elimination of cardiac viral load, protection of myocytes from injury, decrease in inflammatory cell infiltration, and attenuation of intraventricular thrombus formation. Treatment with 10 MIU/kg mIFN-{alpha}2 resulted in a similar level of efficacy as that induced by 5 MIU/kg mIFN-beta, with the exception that mIFN-{alpha}2 did not reduce cardiac CVB3 mRNA. However, mIFN-{alpha}2 , but not any dose group of mIFN-beta, significantly attenuated CVB3-induced epicarditis. These data demonstrate antiviral effects for both mIFN-beta and mIFN-{alpha}2, which lead to protection of the mice from CVB3-induced myocarditis. However, the potential mechanisms leading to a differential host response for the two isoforms of mIFN remain to be elucidated.

viral cardiomyopathy; myocyte infection; antiviral action; immunomodulation


Address for reprint requests and other correspondence: Y.-X. Wang, Bayer Health Care Pharmaceuticals, Hematology/Cardiology, 800 Dwight Way, B28A, R320, PO Box 1986, Berkeley, CA 94701-1986 (e-mail: jim.wang{at}bayer.com)






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