ith more than 53 million confirmed cases of COVID-19 and 1.3 million associated deaths worldwide (World Health Organization, 13 November 2020), there is an urgent need to understand the molecular mechanism of infection and disease to identify patients' susceptibilities and targets for therapeutic intervention. ACE2 is the main viral entry point for coronavirus N63, SARS-CoV and SARS-CoV-2, which cause severe acute respiratory syndromes, the last being responsible for COVID-19 in humans 1-4. ACE2 binds to the S1 domain of trimeric SARS-CoV spike (S) glycoprotein 1 and SARS-CoV-2 S protein 5 , which is primed by TMPRSS2 (ref. 6). Cellular entry of SARS-CoV is dependent on the extracellular domain of ACE2 being cleaved by TMPRSS2 protease at Arg 697 and Lys 716, and the transmembrane domain of ACE2 internalized with the virus 7-9. ACE2 is a carboxypeptidase with several known physiological functions including regulation of blood pressure, salt and water balance in mammals 10,11 , amino acid uptake in the small intestine 12,13 , and glucose homeostasis and pancreatic β-cell function 14,15. Interestingly, ACE2 has been suggested to play an important role in protection from acute lung injury 16-19. ACE2 expression in different tissues is controlled by multiple promoter elements 20-22. In human nasal epithelia and lung tissue, ACE2 expression has been reported to be interferon (IFN) regulated, with evidence of STAT1-, STAT3-, IRF8-and IRF1-binding sites within the ACE2 promoter 23. Activation of IFN-responsive genes is an important antiviral defense pathway in humans, and both interferon and influenza exposure have been reported to increase ACE2 expression in the human airway 23. Bulk and single-cell RNA-sequencing (scRNA-seq) data 24 detect low-level expression of ACE2 in multiple tissues 25. ACE2 expression in the airways is relatively high in nasal epithelium and progressively lower in the bronchial and alveolar regions; this expression profile correlates with levels of infection of SARS-CoV-2 isolates from patients in different airway compartments 26. Consistently, SARS-CoV-2 viral loads have been found to be higher in swabs taken from the nose than swabs taken from the throat of COVID-19 patients 27. Highest ACE2 expression is seen in goblet and ciliated cells of the nasal epithelium 25 , and ACE2 protein localizes to the membrane of motile cilia of respiratory tract epithelia 28. Consistent with this, SARS-CoV-2 has been detected in situ in ciliated airway cells and upper airway epithelium, in addition to pulmonary A novel ACE2 isoform is expressed in human respiratory epithelia and is upregulated in response to interferons and RNA respiratory virus infection

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.