A crucial role of angiotensin converting enzyme 2 (ACE2) in SARS coronavirus-induced lung injury.
During several months of 2003, a newly identified illness termed severe acute respiratory syndrome (SARS) spread rapidly through the world. A new coronavirus (SARS-CoV) was identified as the SARS pathogen, which triggered severe pneumonia and acute, often lethal, lung failure. Moreover, among infected individuals influenza such as the Spanish flu and the emergence of new respiratory disease viruses have caused high lethality resulting from acute lung failure. In cell lines, angiotensin-converting enzyme 2 (ACE2) has been identified as a potential SARS-CoV receptor. The high lethality of SARS-CoV infections, its enormous economic and social impact, fears of renewed outbreaks as well as the potential misuse of such viruses as biologic weapons make it paramount to understand the pathogenesis of SARS-CoV. Here we provide the first genetic proof that ACE2 is a crucial SARS-CoV receptor in vivo. SARS-CoV infections and the Spike protein of the SARS-CoV reduce ACE2 expression. Notably, injection of SARS-CoV Spike into mice worsens acute lung failure in vivo that can be attenuated by blocking the renin-angiotensin pathway. These results provide a molecular explanation why SARS-CoV infections cause severe and often lethal lung failure and suggest a rational therapy for SARS and possibly other respiratory disease viruses.
Kuba
Keiji
K
Institute of Molecular Biotechnology of the Austrian Academy of Sciences, Dr. Bohr-gasse 7, A-1030 Vienna, Austria.
Imai
Yumiko
Y
Rao
Shuan
S
Gao
Hong
H
Guo
Feng
F
Guan
Bin
B
Huan
Yi
Y
Yang
Peng
P
Zhang
Yanli
Y
Deng
Wei
W
Bao
Linlin
L
Zhang
Binlin
B
Liu
Guang
G
Wang
Zhong
Z
Chappell
Mark
M
Liu
Yanxin
Y
Zheng
Dexian
D
Leibbrandt
Andreas
A
Wada
Teiji
T
Slutsky
Arthur S
AS
Liu
Depei
D
Qin
Chuan
C
Jiang
Chengyu
C
Penninger
Josef M
JM
D000704:Analysis of Variance; D000085962:Angiotensin-Converting Enzyme 2; D000818:Animals; D002268:Carboxypeptidases / Q000378:metabolism*; D007150:Immunohistochemistry; D008171:Lung Diseases / Q000201:enzymology* / Q000209:etiology / Q000473:pathology; D008562:Membrane Glycoproteins / Q000235:genetics / Q000378:metabolism*; D051379:Mice; D007703:Peptidyl-Dipeptidase A; D045473:Severe acute respiratory syndrome-related coronavirus / Q000235:genetics / Q000378:metabolism*; D045169:Severe Acute Respiratory Syndrome / Q000150:complications / Q000201:enzymology*; D064370:Spike Glycoprotein, Coronavirus; D014759:Viral Envelope Proteins / Q000235:genetics / Q000378:metabolism*
D008562:Membrane Glycoproteins; D064370:Spike Glycoprotein, Coronavirus; D014759:Viral Envelope Proteins; C578557:spike glycoprotein, SARS-CoV; D002268:Carboxypeptidases; D007703:Peptidyl-Dipeptidase A; C000705328:Ace2 protein, mouse; D000085962:Angiotensin-Converting Enzyme 2