A novel isoform of ACE2 is expressed in human nasal and bronchial respiratory epithelia and is upregulated in response to RNA respiratory virus infection

Blume, Cornelia; Jackson, Claire L; Spalluto, Cosma Mirella; Legebeke, Jelmer; Nazlamova, Liliya; Conforti, Franco; Perotin-Collard, Jeanne-Marie; Frank, Martin; Crispin, Max; Coles, Janice; Thompson, James; Ridley, Robert A; Dean, Lareb S N; Loxham, Matthew; Azim, Adnan; Tariq, Kamran; Johnston, David; Skipp, Paul J; Djukanovic, Ratko; Baralle, Diana; McCormick, Chris; Davies, Donna E; Lucas, Jane S; Wheway, Gabrielle; Mennella, Vito

Angiotensin-converting enzyme 2 (ACE2) is the main entry point in the airways for SARS-CoV-2. ACE2 binding to SARS-CoV-2 protein Spike triggers viral fusion with the cell membrane, resulting in viral RNA genome delivery into the host. Despite ACE2’s critical role in SARS-CoV-2 infection, an understanding of ACE2 expression, including in response to viral infection, remains unclear. Until now ACE2 was thought to encode five transcripts and one 805 amino acid protein. Here we identify a novel short isoform of ACE2. Short ACE2 is expressed in the airway epithelium, the main site of SARS-CoV-2 infection; it is substantially upregulated in response to interferon stimulation and RV infection, but not in response to SARS-CoV-2 infection, and it shows differential regulation in asthma patients. This short isoform lacks SARS-CoV-2 spike glycoprotein high-affinity binding sites and altogether, our data are consistent with a model where short ACE2 may influence host susceptibility to SARS-CoV-2 infection.