Differential expression in humans of the viral entry receptor ACE2 compared with the short deltaACE2 isoform lacking SARS-CoV-2 binding sites

Sci Rep. 2021 Dec 21;11(1):24336. doi: 10.1038/s41598-021-03731-9.


ACE2 is a membrane protein that regulates the cardiovascular system. Additionally, ACE2 acts as a receptor for host cell infection by human coronaviruses, including SARS-CoV-2 that emerged as the cause of the on-going COVID-19 pandemic and has brought unprecedented burden to economy and health. ACE2 binds the spike protein of SARS-CoV-2 with high affinity and shows little variation in amino acid sequence meaning natural resistance is rare. The discovery of a novel short ACE2 isoform (deltaACE2) provides evidence for inter-individual differences in SARS-CoV-2 susceptibility and severity, and likelihood of developing subsequent 'Long COVID'. Critically, deltaACE2 loses SARS-CoV-2 spike protein binding sites in the extracellular domain, and is predicted to confer reduced susceptibility to viral infection. We aimed to assess the differential expression of full-length ACE2 versus deltaACE2 in a panel of human tissues (kidney, heart, lung, and liver) that are implicated in COVID-19, and confirm ACE2 protein in these tissues. Using dual antibody staining, we show that deltaACE2 localises, and is enriched, in lung airway epithelia and bile duct epithelia in the liver. Finally, we also confirm that a fluorescently tagged SARS-CoV-2 spike protein monomer shows low binding at lung and bile duct epithelia where dACE2 is enriched.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Angiotensin-Converting Enzyme 2 / chemistry
  • Angiotensin-Converting Enzyme 2 / genetics
  • Angiotensin-Converting Enzyme 2 / metabolism*
  • Bile Ducts / metabolism
  • Bile Ducts / virology
  • Binding Sites
  • COVID-19 / pathology
  • COVID-19 / virology
  • Humans
  • Lung / metabolism
  • Lung / virology
  • Microscopy, Fluorescence, Multiphoton
  • Protein Binding
  • Protein Isoforms / chemistry
  • Protein Isoforms / genetics
  • Protein Isoforms / metabolism
  • Receptors, Virus / chemistry
  • Receptors, Virus / metabolism
  • SARS-CoV-2 / isolation & purification
  • SARS-CoV-2 / physiology*
  • Spike Glycoprotein, Coronavirus / chemistry
  • Spike Glycoprotein, Coronavirus / metabolism*
  • Virus Internalization


  • Protein Isoforms
  • Receptors, Virus
  • Spike Glycoprotein, Coronavirus
  • spike protein, SARS-CoV-2
  • Angiotensin-Converting Enzyme 2