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Published Online April 14, 2005
Science DOI: 10.1126/science.1110656

Reports

Submitted on February 3, 2005
Accepted on March 30, 2005

Endosomal Proteolysis of the Ebola Virus Glycoprotein Is Necessary for Infection

Kartik Chandran 1, Nancy J. Sullivan 2, Ute Felbor 3, Sean P. Whelan 4, James M. Cunningham 5*

1 Department of Medicine, Brigham and Women's Hospital and Harvard Medical School, Boston, MA 02115, USA.
2 Vaccine Research Center, National Institute of Allergy and Infectious Diseases, National Institutes of Health, Bethesda, MD 20892, USA.
3 Institute of Human Genetics, Biozentrum, Am Hubland, D-97074 Würzburg, Germany.
4 Department of Microbiology and Molecular Genetics, Harvard Medical School, Boston, MA 02115, USA.
5 Department of Medicine, Brigham and Women's Hospital and Harvard Medical School, Boston, MA 02115, USA; Department of Microbiology and Molecular Genetics, Harvard Medical School, Boston, MA 02115, USA.

* To whom correspondence should be addressed.
James M. Cunningham , E-mail: jcunningham{at}rics.bwh.harvard.edu

Ebola virus (EboV) causes rapidly fatal hemorrhagic fever in humans, and there is currently no effective treatment. We found that infection of Vero cells by vesicular stomatitis viruses bearing the EboV glycoprotein (GP) requires the activity of endosomal cysteine proteases. Using selective protease inhibitors and protease-deficient cell lines, we identified an essential role for cathepsin B (CatB), and an accessory role for cathepsin L (CatL) in EboV GP-dependent entry. Biochemical studies demonstrate that CatB and CatL mediate entry by carrying out proteolysis of the EboV glycoprotein subunit GP1 and support a multistep mechanism that explains the relative contributions of these enzymes to infection. CatB and CatB/CatL inhibitors diminish multiplication of infectious EboV-Zaire in cultured cells and may merit investigation as anti-EboV drugs.


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