Potential detrimental role of soluble ACE2 in severe COVID-19 comorbid patients

Rev Med Virol. 2021 Sep;31(5):1-12. doi: 10.1002/rmv.2213. Epub 2021 Jan 10.


Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) enters the host cell by binding to angiotensin-converting enzyme 2 (ACE2) receptor. Other important proteins involved in this process include disintegrin and metalloproteinase domain-containing protein 17 (ADAM17) also known as tumour necrosis factor-α-converting enzyme and transmembrane serine protease 2. ACE2 converts angiotensin II (Ang II) to angiotensin (1-7), to balance the renin angiotensin system. Membrane-bound ACE2 ectodomain shedding is mediated by ADAM17 upon viral spike binding, Ang II overproduction and in several diseases. The shed soluble ACE2 (sACE2) retains its catalytic activity, but its precise role in viral entry is still unclear. Therapeutic sACE2 is claimed to exert dual effects; reduction of excess Ang II and blocking viral entry by masking the spike protein. Nevertheless, the paradox is why SARS-CoV-2 comorbid patients struggle to attain such benefit in viral infection despite having a high amount of sACE2. In this review, we discuss the possible detrimental role of sACE2 and speculate on a series of events where protease primed or non-primed virus-sACE2 complex might enter the host cell. As extracellular virus can bind many sACE2 molecules, sACE2 level could be reduced drastically upon endocytosis by the host cell. A consequential rapid rise in Ang II level could potentially aggravate disease severity through Ang II-angiotensin II receptor type 1 (AT1R) axis in comorbid patients. Hence, monitoring sACE2 and Ang II level in coronavirus disease 2019 comorbid patients are crucial to ensure safe and efficient intervention using therapeutic sACE2 and vaccines.

Keywords: COVID-19; SARS-CoV-2 entry; soluble ACE2.

Publication types

  • Review

MeSH terms

  • ADAM17 Protein / genetics
  • ADAM17 Protein / metabolism
  • Angiotensin I / metabolism
  • Angiotensin II / metabolism
  • Angiotensin-Converting Enzyme 2 / genetics
  • Angiotensin-Converting Enzyme 2 / metabolism*
  • Animals
  • COVID-19 / enzymology*
  • COVID-19 / genetics
  • COVID-19 / virology
  • Comorbidity
  • Humans
  • Peptide Fragments / metabolism
  • SARS-CoV-2 / physiology


  • Peptide Fragments
  • Angiotensin II
  • Angiotensin I
  • Angiotensin-Converting Enzyme 2
  • ADAM17 Protein
  • ADAM17 protein, human
  • angiotensin I (1-7)