SARS coronavirus, but not human coronavirus NL63, utilizes cathepsin L to infect ACE2-expressing cells.
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.
Huang
I-Chueh
IC
Pulmonary Division, Children's Hospital, Children's Hospital Laboratory of Molecular Medicine, Harvard Medical School, Boston, Massachusetts 02115, USA.
Bosch
Berend Jan
BJ
Li
Fang
F
Li
Wenhui
W
Lee
Kyoung Hoa
KH
Ghiran
Sorina
S
Vasilieva
Natalya
N
Dermody
Terence S
TS
Harrison
Stephen C
SC
Dormitzer
Philip R
PR
Farzan
Michael
M
Rottier
Peter J M
PJ
Choe
Hyeryun
H
D000085962:Angiotensin-Converting Enzyme 2; D000818:Animals; D002268:Carboxypeptidases / Q000378:metabolism*; D056668:Cathepsin L; D002403:Cathepsins / Q000378:metabolism / Q000502:physiology*; D002460:Cell Line; D002522:Chlorocebus aethiops; D017934:Coronavirus / Q000502:physiology*; D003546:Cysteine Endopeptidases / Q000378:metabolism / Q000502:physiology*; D011992:Endosomes / Q000378:metabolism; D049452:Green Fluorescent Proteins / Q000378:metabolism; D006801:Humans; D008247:Lysosomes / Q000201:enzymology; D008562:Membrane Glycoproteins / Q000378:metabolism; D007703:Peptidyl-Dipeptidase A; D012190:Retroviridae / Q000235:genetics; D045473:Severe acute respiratory syndrome-related coronavirus / Q000502:physiology*; D013045:Species Specificity; D014709:Vero Cells; D014759:Viral Envelope Proteins / Q000378:metabolism
C028391:G protein, vesicular stomatitis virus; D008562:Membrane Glycoproteins; D014759:Viral Envelope Proteins; D049452:Green Fluorescent Proteins; D002268:Carboxypeptidases; D002403:Cathepsins; D007703:Peptidyl-Dipeptidase A; C000705307:ACE2 protein, human; D000085962:Angiotensin-Converting Enzyme 2; D003546:Cysteine Endopeptidases; C534281:CTSL protein, human; D056668:Cathepsin L