ACE2-like carboxypeptidase B38-CAP protects from SARS-CoV-2-induced lung injury

Tomokazu Yamaguchi, Midori Hoshizaki, Takafumi Minato, Satoru Nirasawa, Masamitsu N. Asaka, Mayumi Niiyama, Masaki Imai, Akihiko Uda, Jasper Fuk-Woo Chan, Saori Takahashi, Jianbo An, Akari Saku, Ryota Nukiwa, Daichi Utsumi, Maki Kiso, Atsuhiro Yasuhara, Vincent Kwok-Man Poon, Chris Chung-Sing Chan, Yuji Fujino, Satoru Motoyama, Satoshi Nagata, Josef M. Penninger, Haruhiko Kamada, Kwok-Yung Yuen, Wataru Kamitani, Ken Maeda, Yoshihiro Kawaoka, Yasuhiro Yasutomi, Yumiko Imai and Keiji Kuba ()
Additional contact information
Tomokazu Yamaguchi: Akita University Graduate School of Medicine
Midori Hoshizaki: Akita University Graduate School of Medicine
Takafumi Minato: Akita University Graduate School of Medicine
Satoru Nirasawa: Japan International Research Center for Agricultural Sciences
Masamitsu N. Asaka: Tsukuba Primate Research Center, NIBIOHN
Mayumi Niiyama: Laboratory of Biopharmaceutical Research, NIBIOHN
Masaki Imai: University of Tokyo
Akihiko Uda: National Institute of Infectious Diseases
Jasper Fuk-Woo Chan: The University of Hong Kong
Saori Takahashi: Akita Research Institute of Food and Brewing
Jianbo An: Akita University Graduate School of Medicine
Akari Saku: Akita University Graduate School of Medicine
Ryota Nukiwa: National Institute of Biomedical Innovation, Health and Nutrition (NIBIOHN)
Daichi Utsumi: Tsukuba Primate Research Center, NIBIOHN
Maki Kiso: University of Tokyo
Atsuhiro Yasuhara: University of Tokyo
Vincent Kwok-Man Poon: The University of Hong Kong
Chris Chung-Sing Chan: The University of Hong Kong
Yuji Fujino: Osaka University Graduate School of Medicine
Satoru Motoyama: Akita University Graduate School of Medicine
Satoshi Nagata: Laboratory of Antibody Design, NIBIOHN
Josef M. Penninger: University of British Columbia
Haruhiko Kamada: Laboratory of Biopharmaceutical Research, NIBIOHN
Kwok-Yung Yuen: The University of Hong Kong
Wataru Kamitani: Gunma University
Ken Maeda: National Institute of Infectious Diseases
Yoshihiro Kawaoka: University of Tokyo
Yasuhiro Yasutomi: Tsukuba Primate Research Center, NIBIOHN
Yumiko Imai: National Institute of Biomedical Innovation, Health and Nutrition (NIBIOHN)
Keiji Kuba: Akita University Graduate School of Medicine

Nature Communications, 2021, vol. 12, issue 1, 1-13

Abstract: Abstract Angiotensin-converting enzyme 2 (ACE2) is a receptor for cell entry of SARS-CoV-2, and recombinant soluble ACE2 protein inhibits SARS-CoV-2 infection as a decoy. ACE2 is a carboxypeptidase that degrades angiotensin II, thereby improving the pathologies of cardiovascular disease or acute lung injury. Here we show that B38-CAP, an ACE2-like enzyme, is protective against SARS-CoV-2-induced lung injury. Endogenous ACE2 expression is downregulated in the lungs of SARS-CoV-2-infected hamsters, leading to elevation of angiotensin II levels. Recombinant Spike also downregulates ACE2 expression and worsens the symptoms of acid-induced lung injury. B38-CAP does not neutralize cell entry of SARS-CoV-2. However, B38-CAP treatment improves the pathologies of Spike-augmented acid-induced lung injury. In SARS-CoV-2-infected hamsters or human ACE2 transgenic mice, B38-CAP significantly improves lung edema and pathologies of lung injury. These results provide the first in vivo evidence that increasing ACE2-like enzymatic activity is a potential therapeutic strategy to alleviate lung pathologies in COVID-19 patients.

Date: 2021
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DOI: 10.1038/s41467-021-27097-8

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