Clarifying the controversial risk-benefit profile of soluble ACE2 in COVID-19

To the Editor:In the timely report on age and gender differences in soluble angiotensin-converting enzyme 2 (sACE2) among COVID-19 patients, Sward et al. [1] elegantly showed that adults and men exhibited higher plasma concentrations of sACE2 relative to children and women, respectively.They assumed that high sACE2 levels reflect high membrane-bound ACE2 (mACE2) and/or ADAM-17 expression levels, thereby connoting a high susceptibility for COVID-19 infection.Yet, this has not been proven conclusively.First, mACE2 rather than sACE2 functions as the key portal of entry for SARS-CoV-2.Unlike plasma sACE2 which lacks critical membrane machinery for cell invasion, mACE2 homodimers dock with S-glycoprotein trimers of SARS-CoV-2 and cleave S into S1 (which binds ACE2 peptidase domain) and S2 (responsible for membrane fusion) for subsequent receptor-mediated endocytosis of virion particles by membrane-bound serine protease TMPRSS2 and lysosomal L-cathepsin [2].sACE2 probably plays no role in orchestrating the cellular entry of SARS-CoV-2 without the molecular cooperativity of TMPRSS2 and Lcathepsin.Secondly, plasma ACE2 arises from shedding of mACE2 via ADAM-17 protease induced by angiotensin-II acting via AT-1 receptors [3].Blockade of AT-1 receptors by angiotensin-receptor blockers (ARBs) inhibits this process and leads to higher mACE2 expression and lower sACE2, a situation that fueled initial