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

• Published in: Nature communications Vol. 12; no. 1; p. 6791
• Main Authors: Yamaguchi, Tomokazu, Hoshizaki, Midori, Minato, Takafumi, Nirasawa, Satoru, Asaka, Masamitsu N., Niiyama, Mayumi, Imai, Masaki, Uda, Akihiko, Chan, Jasper Fuk-Woo, Takahashi, Saori, An, Jianbo, Saku, Akari, Nukiwa, Ryota, Utsumi, Daichi, Kiso, Maki, Yasuhara, Atsuhiro, Poon, Vincent Kwok-Man, Chan, Chris Chung-Sing, Fujino, Yuji, Motoyama, Satoru, Nagata, Satoshi, Penninger, Josef M., Kamada, Haruhiko, Yuen, Kwok-Yung, Kamitani, Wataru, Maeda, Ken, Kawaoka, Yoshihiro, Yasutomi, Yasuhiro, Imai, Yumiko, Kuba, Keiji
• Format: Journal Article
• Language: English
• Published: London Nature Publishing Group UK 23.11.2021; Nature Publishing Group; Nature Portfolio
• Subjects: 38/88; 631/326/596/4130; 631/45/611; 64/60; 692/699/1785/3193; 82/1; 82/51; 96; ACE2; Acute Lung Injury; Angiotensin; Angiotensin II; Angiotensin-converting enzyme 2; Angiotensin-Converting Enzyme 2 - metabolism; Animal models; Animals; Carboxypeptidase; Carboxypeptidases; Cardiovascular diseases; Chlorocebus aethiops; COVID-19; COVID-19 - drug therapy; COVID-19 - pathology; COVID-19 - prevention & control; Cricetinae; Disease Models, Animal; Edema; Enzymatic activity; Enzymes; Female; Hamsters; Humanities and Social Sciences; Humans; Infections; Injuries; Lung - pathology; Lung diseases; Lung Injury - prevention & control; Lungs; Male; Mice; Mice, Transgenic; multidisciplinary; Nitric oxide; Peptidyl-dipeptidase A; Proteins; Pulmonary Edema - pathology; Pulmonary Edema - prevention & control; Receptors; SARS-CoV-2 - drug effects; Science; Science (multidisciplinary); Severe acute respiratory syndrome; Severe acute respiratory syndrome coronavirus 2; Signs and symptoms; Spike Glycoprotein, Coronavirus - drug effects; Transgenic mice; Vero Cells; Viral diseases; Virus Internalization - drug effects; Viruses
• ISSN: 2041-1723; 2041-1723
• DOI: 10.1038/s41467-021-27097-8

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. Endogenous ACE2 is a receptor for SARS-CoV-2 and a recombinant soluble ACE2 protein can inhibit SARS-CoV-2 infection acting as a decoy. Here the authors show that B38-CAP, an ACE2-like enzyme but not a decoy for the virus, is protective against SARS-CoV-2-induced lung injury in animal models.