ACE2 Expression is Increased in the Lungs of Patients with Comorbidities Associated with Severe COVID-19

Pinto, Bruna G G; Oliveira, Antônio Edson Rocha; Singh, Youvika; Jimenez, Leandro; Gonçalves, André Nicolau Aquime; Ogava, Rodrigo L T; Creighton, Rachel; Peron, Jean Pierre Schatzmann; Nakaya, Hidehiko

doi:10.1101/2020.03.21.20040261

Cited by 116 publications

(152 citation statements)

References 45 publications

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“…Other strategies aim to use purified soluble recombinant ACE2, or ACE2+-small extracellular vesicles 59 to 'intercept' the virus before entry into host cells, avoiding infection. Our discovery also has implications for the numerous studies reporting on ACE2 expression levels and differences in levels of expression along airways, across age groups and disease groups 29,46,60,61 including COVID-19 disease severity 61,62 . This finding should be considered in in choice of Alignment files were assessed for saturation of known splice junctions using RSeqQC v3.0.1 71 .…”

Section: Discussionmentioning

confidence: 82%

A novel isoform ofACE2is expressed in human nasal and bronchial respiratory epithelia and is upregulated in response to RNA respiratory virus infection

Blume

Jackson

Spalluto

et al. 2020

Preprint

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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.

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Section: Discussionmentioning

confidence: 82%

A novel isoform ofACE2is expressed in human nasal and bronchial respiratory epithelia and is upregulated in response to RNA respiratory virus infection

Blume

Jackson

Spalluto

et al. 2020

Preprint

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“…More importantly, ACE2 expression was increased in the lungs of severe COVID-19 patients with comorbidities, compared to control individuals 18,25 . The enhanced ACE2 activity to cleave Ang II upon SARS-CoV-2 spike binding might be one of the mechanisms whereby SARS-CoV-2 utilized to boost the expression of ACE2.…”

Section: Discussionmentioning

confidence: 90%

High affinity binding of SARS-CoV-2 spike protein enhances ACE2 carboxypeptidase activity

Sun

2020

Preprint

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AbstractA novel coronavirus (SARS-CoV-2) has emerged to a global pandemic and caused significant damages to public health. Human angiotensin-converting enzyme 2(ACE2) was identified as the entry receptor for SARS-CoV-2. As a carboxypeptidase, ACE2 cleaves many biological substrates besides Ang II to control vasodilatation and permeability. Given the nanomolar high affinity between ACE2 and SARS-CoV-2 spike protein, we wonder how this interaction would affect the enzymatic activity of ACE2. Surprisingly, SARS-CoV-2 trimeric spike protein increased ACE2 proteolytic activity ~3-10 fold when fluorogenic caspase-1 substrate and Bradykinin-analog peptides were used to characterize ACE2 activity. In addition, the enhancement was mediated by ACE2 binding of RBD domain of SARS-CoV-2 spike. These results highlighted the altered activity of ACE2 during SARS-CoV-2 infection and would shed new lights on the pathogenesis of COVID-19 and its complications for better treatments.

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“…Previous studies have evaluated ACE2 expression in the respiratory tract. Studies of ACE2 mRNA transcript abundance have provided conflicting interpretations, as well as a lack of protein validation (12)(13)(14)(15)(16)(17)(18)(19). ACE2 protein studies have been limited by a paucity of lung tissue substrates and reports that have yielded contradictory results (20-23) (Supplemental Table 1).…”

Section: Introductionmentioning

confidence: 99%

Heterogeneous expression of the SARS-Coronavirus-2 receptor ACE2 in the human respiratory tract

Bezara

Thurman

Pezzulo

et al. 2020

Preprint

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15Running title: Expression of ACE2 in the human respiratory tract 16 17 Impact: The mapping of ACE2, the receptor for SARS-CoV-2, to specific anatomical regions 18 and to particular cell types in the human respiratory tract will help guide future studies and 19 provide molecular targets for antiviral therapies. We saw no increase of receptor expression in 20 the presence of known risk factors for severe coronavirus disease 2019. 21 22 Abstract: 35 Rationale: Zoonotically transmitted coronaviruses are responsible for three disease 36 outbreaks since 2002, including the current coronavirus disease 2019 pandemic, caused by 37 SARS-CoV-2. Its efficient transmission and range of disease severity raise questions regarding 38 the contributions of virus-receptor interactions. ACE2 is a host ectopeptidase and the cellular 39 receptor for SARS-CoV-2. Receptor expression on the cell surface facilitates viral binding and 40 entry. However, reports of the abundance and distribution of ACE2 expression in the respiratory 41 tract are limited and conflicting. Objectives: To determine ACE2 expression in the human 42 respiratory tract and its association with demographic and clinical characteristics. Methods: 43Here, we systematically examined human upper and lower respiratory tract cells using single-cell 44 RNA sequencing and immunohistochemistry to determine where the receptor is expressed. 45Measurements and main results: Our results reveal that ACE2 expression is highest within the 46 sinonasal cavity and pulmonary alveoli, sites of presumptive viral transmission and severe 47 disease development, respectively. In the lung parenchyma where severe disease occurs, ACE2 48 was found on the apical surface of a small subset of alveolar type II cells. We saw no increase of 49 receptor expression in the presence of known risk factors for severe coronavirus disease 2019. 50Conclusions: The mapping of ACE2 to specific anatomical regions and to particular cell types in 51 the respiratory tract will help guide future studies and provide molecular targets for antiviral 52 therapies. 53 54 Word count: 223 55

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ACE2 Expression is Increased in the Lungs of Patients with Comorbidities Associated with Severe COVID-19

Cited by 116 publications

References 45 publications

A novel isoform ofACE2is expressed in human nasal and bronchial respiratory epithelia and is upregulated in response to RNA respiratory virus infection

A novel isoform ofACE2is expressed in human nasal and bronchial respiratory epithelia and is upregulated in response to RNA respiratory virus infection

High affinity binding of SARS-CoV-2 spike protein enhances ACE2 carboxypeptidase activity

Heterogeneous expression of the SARS-Coronavirus-2 receptor ACE2 in the human respiratory tract

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