Nature Medicine
11, 875 - 879 (2005)
Published online: 10 July 2005; | doi:10.1038/nm1267
A crucial role of angiotensin converting enzyme 2 (ACE2) in SARS coronavirus−induced lung injuryKeiji Kuba1, 7, Yumiko Imai1, 7, Shuan Rao2, 7, Hong Gao3, Feng Guo2, Bin Guan2, Yi Huan2, Peng Yang2, Yanli Zhang2, Wei Deng3, Linlin Bao3, Binlin Zhang3, Guang Liu2, Zhong Wang4, Mark Chappell5, Yanxin Liu2, Dexian Zheng2, Andreas Leibbrandt1, Teiji Wada1, Arthur S Slutsky6, Depei Liu2, Chuan Qin3, Chengyu Jiang2
& Josef M Penninger11
Institute of Molecular Biotechnology of the Austrian Academy of Sciences, Dr. Bohr-gasse 7, A-1030
Vienna, Austria. 2
National Laboratory of Medical Molecular Biology, Institute of Basic Medical Sciences, Chinese Academy of Medical Sciences & Peking Union Medical College, 5 Dongdan Santiao, Beijing
100005, China. 3
Institute of Laboratory Animal Sciences, Chinese Academy of Medical Sciences & Peking Union Medical College, 5 Dongdan Santiao, Beijing
100005, China. 4
Peking Union Medical College Hospital, Chinese Academy of Medical Sciences & Peking Union Medical College, 5 Dongdan Santiao, Beijing
100005, China. 5
The Hypertension and Vascular Disease Center, Wake Forest University School of Medicine, Gray Building, G054 Medical Center Boulevard, Winston-Salem, North Carolina
27157-1032, USA. 6
Department of Medicine and Interdepartmental Division of Critical Care, University of Toronto; St. Michael's Hospital, 30 Bond Street, Toronto, M5B 1W8, Canada. 7
These authors contributed equally to this work.
Correspondence should be addressed to Chengyu Jiang jiang@pumc.edu.cn During several months of 2003, a newly identified illness termed severe acute respiratory syndrome (SARS) spread rapidly through the world1,
2,
3. A new coronavirus (SARS-CoV) was identified as the SARS pathogen4,
5,
6,
7, which triggered severe pneumonia and acute, often lethal, lung failure8. Moreover, among infected individuals influenza such as the Spanish flu9,
10 and the emergence of new respiratory disease viruses11,
12 have caused high lethality resulting from acute lung failure13. In cell lines, angiotensin-converting enzyme 2 (ACE2) has been identified as a potential SARS-CoV receptor14. 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.
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