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J. Biol. Chem., Vol. 281, Issue 6, 3198-3203, February 10, 2006

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SARS Coronavirus, but Not Human Coronavirus NL63, Utilizes Cathepsin L to Infect ACE2-expressing Cells^*

I-Chueh Huang¹, Berend Jan Bosch¹, Fang Li^¶, Wenhui Li^||, Kyoung Hoa Lee, Sorina Ghiran, Natalya Vasilieva, Terence S. Dermody^**, Stephen C. Harrison^¶, Philip R. Dormitzer^¶, Michael Farzan^||, Peter J. M. Rottier², and Hyeryun Choe³

From the Pulmonary Division, Children's Hospital, ^¶Children's Hospital Laboratory of Molecular Medicine, Harvard Medical School, Boston, Massachusetts 02115, the Virology Division, Department of Infectious Diseases & Immunology, Faculty of Veterinary Medicine, and Institute of Biomembranes, Utrecht University, Yalelaan 1, 3584 CL Utrecht, The Netherlands, the ^||Department of Microbiology and Molecular Genetics, Harvard Medical School, New England Primate Research Center, Southborough, Massachusetts 01772, and the ^**Department of Microbiology and Immunology, Elizabeth B. Lamb Center for Pediatric Research, Vanderbilt University School of Medicine, Nashville, Tennessee 37232

Viruses require specific cellular receptors to infect their target cells. Angiotensin-converting enzyme 2 (ACE2) is a cellular receptor for two divergent coronaviruses, SARS coronavirus (SARS-CoV) and human coronavirus NL63 (HCoV-NL63). In addition to hostcell receptors, lysosomal cysteine proteases are required for productive infection by some viruses. Here we show that SARS-CoV, but not HCoV-NL63, utilizes the enzymatic activity of the cysteine protease cathepsin L to infect ACE2-expressing cells. Inhibitors of cathepsin L blocked infection by SARS-CoV and by a retrovirus pseudotyped with the SARS-CoV spike (S) protein but not infection by HCoV-NL63 or a retrovirus pseudotyped with the HCoV-NL63 S protein. Expression of exogenous cathepsin L substantially enhanced infection mediated by the SARS-CoV S protein and by filovirus GP proteins but not by the HCoV-NL63 S protein or the vesicular stomatitis virus G protein. Finally, an inhibitor of endosomal acidification had substantially less effect on infection mediated by the HCoV-NL63 S protein than on that mediated by the SARS-CoV S protein. Our data indicate that two coronaviruses that utilize a common receptor nonetheless enter cells through distinct mechanisms.

Received for publication, August 1, 2005 , and in revised form, December 8, 2005.

Note Added in Proof—While this manuscript was under review, Simmons et al. (Simmons, G., Gosalia, D. N., RenneKamp, A. J., Reeves, J. D., Diamond, S. L., and Bates, P. (2005) Proc. Natl. Acad. Sci. U. S. A. 102, 11876–11882) published results simiar to those herein.

^* This work was supported by Grants AI43891 (to H. C.) and AI0616101 (to M. F.) from the National Institutes of Health and Grant SP22-CT-2004-511060 (to P. J. M. R.) from the European Union. The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked "advertisement" in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.

The on-line version of this article (available at http://www.jbc.org) contains supplemental Fig. 1.

¹ These authors contributed equally to this article.

² To whom correspondence may be addressed. E-mail: p.j.m.rottier{at}vet.uu.nl. ³ To whom correspondence may be addressed. E-mail: hyeryun.choe{at}childrens.harvard.edu.

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