Endosomal proteolysis of the Ebola virus glycoprotein is necessary for infection.
Ebola virus (EboV) causes rapidly fatal hemorrhagic fever in humans and there is currently no effective treatment. We found that the infection of African green monkey kidney (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 GP subunit GP1 and support a multistep mechanism that explains the relative contributions of these enzymes to infection. CatB and CatB/CatL inhibitors diminish the multiplication of infectious EboV-Zaire in cultured cells and may merit investigation as anti-EboV drugs.
Chandran
Kartik
K
Department of Medicine, Brigham and Women's Hospital and Harvard Medical School, Boston, MA 02115, USA.
Sullivan
Nancy J
NJ
Felbor
Ute
U
Whelan
Sean P
SP
Cunningham
James M
JM
D000818:Animals; D002401:Cathepsin B / Q000037:antagonists & inhibitors / Q000378:metabolism*; D056668:Cathepsin L; D002403:Cathepsins / Q000037:antagonists & inhibitors / Q000378:metabolism*; D002460:Cell Line; D002478:Cells, Cultured; D002522:Chlorocebus aethiops; D003546:Cysteine Endopeptidases / Q000378:metabolism*; D015853:Cysteine Proteinase Inhibitors / Q000494:pharmacology; D029043:Ebolavirus / Q000378:metabolism / Q000502:physiology*; D011992:Endosomes / Q000378:metabolism*; D006863:Hydrogen-Ion Concentration; D051379:Mice; D014709:Vero Cells; D014721:Vesicular stomatitis Indiana virus / Q000235:genetics / Q000502:physiology; D014759:Viral Envelope Proteins / Q000378:metabolism*; D014771:Virion / Q000502:physiology
D015853:Cysteine Proteinase Inhibitors; D014759:Viral Envelope Proteins; C113189:envelope glycoprotein, Ebola virus; D002403:Cathepsins; D003546:Cysteine Endopeptidases; D002401:Cathepsin B; C534281:CTSL protein, human; D056668:Cathepsin L; C534278:Ctsl protein, mouse