Suppression of SARS-CoV-2-induced lung injury by ACE2-like carboxypeptidase B38-CAP in COVID-19 mouse model

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 the carboxypeptidase to degrade angiotensin II (Ang II) to angiotensin 1-7 and improves the pathologies of cardiovascular disease and acute lung injury. To address whether the carboxypeptidase enzymatic activity of ACE2 is protective against COVID-19, we investigated the effects of B38-CAP, an ACE2-like enzyme, on SARS-CoV-2-induced lung injury. Expression of ACE2 protein was significantly downregulated in the lungs of SARS-CoV-2-infected hamsters. Recombinant S1 domain or receptor-binding domain (RBD) of the SARS-CoV-2 Spike protein also directly downregulated ACE2 expression and elevated Ang II levels and considerably worsened acid-induced lung injury in hamsters. Treatment with B38-CAP downregulated Spike RBDinduced high Ang II levels, severe inflammation and pulmonary edema through its ACE2-like enzymatic activity. Consistently, elevated cytokine mRNA levels and impaired lung functions were improved by B38-CAP treatment. Moreover, in SARS-CoV-2-infected humanized ACE2 transgenic mice, B38-CAP significantly improved the pathologies of lung injury, alleviated the cytokine storms and downregulated viral RNA levels. These results provide the first experimental in vivo evidence that increasing ACE2-like enzymatic activity is a potential and powerful therapeutic strategy for lung pathologies in COVID-19.

The relationship between gut microbiota and COVID-19 progression: new insights into immunopathogenesis and treatment

“…ACE2 downregulation can inhibit the uptake of tryptophan, which reduces the antimicrobial peptide formation by Paneth cells, culminating in gut microbiota dysbiosis and gastrointestinal disorders related to intestinal microbiota imbalance (52). Previous reports showed that SARS-CoV-2 could decrease ACE2 expression in intestinal epithelial cells (53)(54)(55). It is thus inferred that SARS-CoV-2 infection contributes to gut microbiota dysfunction by downregulating ACE2.…”