Cathepsins B and L activate Ebola but not Marburg virus glycoproteins for efficient entry into cell lines and macrophages independent of TMPRSS2 expression.
Ebola (EBOV) and Marburg virus (MARV) cause severe hemorrhagic fever. The host cell proteases cathepsin B and L activate the Zaire ebolavirus glycoprotein (GP) for cellular entry and constitute potential targets for antiviral intervention. However, it is unclear if different EBOV species and MARV equally depend on cathepsin B/L activity for infection of cell lines and macrophages, important viral target cells. Here, we show that cathepsin B/L inhibitors markedly reduce 293T cell infection driven by the GPs of all EBOV species, independent of the type II transmembrane serine protease TMPRSS2, which cleaved but failed to activate EBOV-GPs. Similarly, a cathepsin B/L inhibitor blocked macrophage infection mediated by different EBOV-GPs. In contrast, MARV-GP-driven entry exhibited little dependence on cathepsin B/L activity. Still, MARV-GP-mediated entry was efficiently blocked by leupeptin. These results suggest that cathepsins B/L promote entry of EBOV while MARV might employ so far unidentified proteases for GP activation.
Institute of Virology, Hannover Medical School, Hannover, Germany.
Kerstin
K
Gnirss
Annika
A
Kühl
Christina
C
Karsten
Ilona
I
Glowacka
Stephanie
S
Bertram
Franziska
F
Kaup
Heike
H
Hofmann
Stefan
S
Pöhlmann
D002401:Cathepsin B / Q000235:genetics / Q000378:metabolism*; D056668:Cathepsin L / Q000235:genetics / Q000378:metabolism*; D002460:Cell Line; D029043:Ebolavirus / Q000235:genetics / Q000502:physiology*; D015971:Gene Expression Regulation, Enzymologic; D006023:Glycoproteins / Q000235:genetics / Q000378:metabolism*; D019142:Hemorrhagic Fever, Ebola / Q000201:enzymology* / Q000235:genetics / Q000821:virology; D006801:Humans; D008264:Macrophages / Q000201:enzymology* / Q000821:virology; D029024:Marburgvirus / Q000235:genetics / Q000502:physiology*; D012697:Serine Endopeptidases / Q000235:genetics* / Q000378:metabolism; D014764:Viral Proteins / Q000235:genetics / Q000378:metabolism*; D053586:Virus Internalization
D006023:Glycoproteins; D014764:Viral Proteins; D012697:Serine Endopeptidases; C421305:TMPRSS2 protein, human; D002401:Cathepsin B; D056668:Cathepsin L