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

Change log
Williams, Thomas L 
Strachan, Gregory 
Macrae, Robyn GC 
Kuc, Rhoda E 
Nyimanu, Duuamene 

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.

Angiotensin-Converting Enzyme 2, Bile Ducts, Binding Sites, COVID-19, Humans, Lung, Microscopy, Fluorescence, Multiphoton, Protein Binding, Protein Isoforms, Receptors, Virus, SARS-CoV-2, Spike Glycoprotein, Coronavirus, Virus Internalization
Journal Title
Sci Rep
Conference Name
Journal ISSN
Volume Title
Springer Science and Business Media LLC
British Heart Foundation (SP/15/7/31561)
Cambridge University Hospitals NHS Foundation Trust (CUH) (unknown)
Wellcome Trust (107715/Z/15/Z)
British Heart Foundation (TG/18/4/33770)
Wellcome Trust (203814/Z/16/Z)
Wellcome Trust (208363/Z/17/Z)
British Heart Foundation (FS/18/46/33663)
British Heart Foundation (FS/17/61/33473D)
Medical Research Council (MC_PC_17230)
British Heart Foundation (None)
This research was funded in whole, or in part by: Wellcome Trust (WT107715/Z/15/Z, A.P.D., and J.J.M.); Wellcome Trust Programme in Metabolic and Cardiovascular Disease (203814/Z/16/A, T.L.W., D.N.), Wellcome Trust Major Award (208363/Z/17/Z) for Imaging Core (G.S.); British Heart Foundation (FS/17/61/33473 A.P.D., R.G.C.M; TG/18/4/33770, A.P.D., J.J.M.; FS/18/46/33663, S.S.). Cambridge Biomedical Research Centre Biomedical Resources Grant (University of Cambridge, Cardiovascular Theme, RG64226). The views expressed are those of the author(s) and not necessarily those of the NIHR or the Department of Health and Social Care.