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Journal of Virology, October 2009, p. 9630-9640, Vol. 83, No. 19
0022-538X/09/$08.00+0     doi:10.1128/JVI.01095-09
Copyright © 2009, American Society for Microbiology. All Rights Reserved.

Genetic and Pharmacologic Alteration of Cathepsin Expression Influences Reovirus Pathogenesis{triangledown}

Elizabeth M. Johnson,1,2 Joshua D. Doyle,1,2 J. Denise Wetzel,2,3 R. Paul McClung,2,3 Nobuhiko Katunuma,4 James D. Chappell,2,3,5 M. Kay Washington,5,6 and Terence S. Dermody1,2,3,6*

Departments of Microbiology and Immunology,1 Pediatrics,3 Pathology,5 Vanderbilt Ingram Cancer Center,6 Elizabeth B. Lamb Center for Pediatric Research, Vanderbilt University School of Medicine, Nashville, Tennessee,2 Institute for Health Sciences, Tokushima Bunri University, Tokushima, Japan4

Received 28 May 2009/ Accepted 21 July 2009

The cathepsin family of endosomal proteases is required for proteolytic processing of several viruses during entry into host cells. Mammalian reoviruses utilize cathepsins B (Ctsb), L (Ctsl), and S (Ctss) for disassembly of the virus outer capsid and activation of the membrane penetration machinery. To determine whether cathepsins contribute to reovirus tropism, spread, and disease outcome, we infected 3-day-old wild-type (wt), Ctsb–/–, Ctsl–/–, and Ctss–/– mice with the virulent reovirus strain T3SA+. The survival rate of Ctsb–/– mice was enhanced in comparison to that of wt mice, whereas the survival rates of Ctsl–/– and Ctss–/– mice were diminished. Peak titers at sites of secondary replication in all strains of cathepsin-deficient mice were lower than those in wt mice. Clearance of the virus was delayed in Ctsl–/– and Ctss–/– mice in comparison to the levels for wt and Ctsb–/– mice, consistent with a defect in cell-mediated immunity in mice lacking cathepsin L or S. Cathepsin expression was dispensable for establishment of viremia, but cathepsin L was required for maximal reovirus growth in the brain. Treatment of wt mice with an inhibitor of cathepsin L led to amelioration of reovirus infection. Collectively, these data indicate that cathepsins B, L, and S influence reovirus pathogenesis and suggest that pharmacologic modulation of cathepsin activity diminishes reovirus disease severity.

* Corresponding author. Mailing address: Lamb Center for Pediatric Research, D7235 MCN, Vanderbilt University School of Medicine, Nashville, TN 37232. Phone: (615) 343-9943. Fax: (615) 343-9723. E-mail: terry.dermody{at}vanderbilt.edu

{triangledown} Published ahead of print on 29 July 2009.

Journal of Virology, October 2009, p. 9630-9640, Vol. 83, No. 19
0022-538X/09/$08.00+0     doi:10.1128/JVI.01095-09
Copyright © 2009, American Society for Microbiology. All Rights Reserved.





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