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A crucial role of angiotensin converting enzyme 2 (ACE2) in SARS coronavirus–induced lung injury

Nature Medicine volume 11, pages 875–879 (2005)Cite this article

Abstract

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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Figure 1: ACE2 is a crucial receptor for SARS-CoV infections in vivo.
Figure 2: Downregulation of ACE2 expression by SARS-CoV infection and SARS-CoV Spike protein.
Figure 3: The SARS-CoV Spike protein enhances the severity of acute lung injury.
Figure 4: SARS-CoV Spike mediates lung injury through modulation of the renin-angiotensin system.

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Acknowledgements

We thank C. Richardson and all members of our laboratory for discussions. We also thank B. Seed for discussion and providing the systems to generate recombinant Spike proteins. We thank Q. Zhu, L. Ruan and L. Zhang for sharing unpublished data of SARS coronavirus infection on mice and protocols of virus infections. This work is supported by the Institute for Molecular Biotechnology of the Austrian Academy of Sciences and the Jubilaeumsfonds of the Austrian National Bank. K.K. is supported by a Marie Curie Fellowship from the EU. C.J. is supported by Beijing Committee of Science and Technology grant H030230010930, National Natural Science Foundation of China innovation group grant 30421003 and SARS donation from Joincare Corporation. A.S. is supported in part by the Canadian Institutes of Health Research and the Canada Foundation for Innovation.

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  1. Keiji Kuba, Yumiko Imai and Shuan Rao: These authors contributed equally to this work.

Authors and Affiliations

  1. Institute of Molecular Biotechnology of the Austrian Academy of Sciences, Dr. Bohr-gasse 7, Vienna, A-1030, Austria

    Keiji Kuba, Yumiko Imai, Andreas Leibbrandt, Teiji Wada & Josef M Penninger

  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

    Shuan Rao, Feng Guo, Bin Guan, Yi Huan, Peng Yang, Yanli Zhang, Guang Liu, Yanxin Liu, Dexian Zheng, Depei Liu & Chengyu Jiang

  3. Institute of Laboratory Animal Sciences, Chinese Academy of Medical Sciences & Peking Union Medical College, 5 Dongdan Santiao, Beijing, 100005, China

    Hong Gao, Wei Deng, Linlin Bao, Binlin Zhang & Chuan Qin

  4. Peking Union Medical College Hospital, Chinese Academy of Medical Sciences & Peking Union Medical College, 5 Dongdan Santiao, Beijing, 100005, China

    Zhong Wang

  5. The Hypertension and Vascular Disease Center, Wake Forest University School of Medicine, Gray Building, G054 Medical Center Boulevard, Winston-Salem, 27157-1032, North Carolina, USA

    Mark Chappell

  6. Department of Medicine and Interdepartmental Division of Critical Care, University of Toronto; St. Michael's Hospital, 30 Bond Street, Toronto, M5B 1W8, Canada

    Arthur S Slutsky

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Corresponding author

Correspondence to Chengyu Jiang.

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Competing interests

The Institute for Molecular Biotechnology of the Austrian Academy of Sciences has applied for a patent on modulating the renin-angiotension system for treatment of lung edema.

Supplementary information

Supplementary Fig. 1

Recombinant Spike-Fc proteins and reduced ACE2 expression by Spike (S318-510)-Fc. (PDF 2890 kb)

Supplementary Table 1 (PDF 31 kb)

Supplementary Methods (PDF 97 kb)

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Kuba, K., Imai, Y., Rao, S. et al. A crucial role of angiotensin converting enzyme 2 (ACE2) in SARS coronavirus–induced lung injury. Nat Med 11, 875–879 (2005). https://doi.org/10.1038/nm1267

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