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
U-BIOPRED cohort n=91 epithelial brushings or biopsies IL-17 High Clinical phenotype Nasal polyps Smoking Antibiotic use Epithelial Gene Expression Profile Clinical phenotype FeNO Exacerbations Gene expression shared with psoriasis IDO1 IL1B DEFB4B S100A8, S100A9 PI3 CXCL3, CXCL8 CXCL10, CCL20 Gene signature SERPINB2 POSTN CLCA1 IL-13 High T cell infiltration Neutrophilia Eosinophilia IL-17-high asthma with features of a psoriasis immunophenotype From a the Respiratory,
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