key: cord-1019884-806tgnt0
authors: Bradding, Peter; Richardson, Matthew; Hinks, Timothy S.C.; Howarth, Peter H.; Choy, David F.; Arron, Joseph R.; Wenzel, Sally E.; Siddiqui, Salman
title: ACE2, TMPRSS2 AND FURIN GENE EXPRESSION IN THE AIRWAYS OF PEOPLE WITH ASTHMA – IMPLICATIONS FOR COVID-19
date: 2020-05-22
journal: J Allergy Clin Immunol
DOI: 10.1016/j.jaci.2020.05.013
sha: a3302a0be252e0ed858742bd6d5a65ce6ca04822
doc_id: 1019884
cord_uid: 806tgnt0

Abstract To-date, there has not been a clear signal suggesting that asthma or treatment with inhaled steroids are a risk factor for severe COVID-19 disease. We have therefore explored ACE2 receptor mRNA expression, and co-factors for Sars-CoV-2 infectivity (TMPRSS2 and furin) in bronchial brushes and biopsies from people with asthma and healthy controls, and looked for relationships between asthma severity, Th2- and IL-17 dependent gene signatures, and clinical demographics (age, sex). We have looked at a cohort of 356 research participants from previously described studies. The only significant association was a positive correlation between ACE2 and IL-17-dependent gene expression, and an inverse correlation between ACE2 and Th2-cytokine-dependent gene expression. These data suggest that differences in ACE2, TMPRSS2 and furin epithelial and airway gene expression are unlikely to confer enhanced COVID-19 pneumonia risk in patients with asthma across all treatment intensities and severity.

To-date, there has not been a clear signal suggesting that asthma or treatment with inhaled steroids 38 are a risk factor for severe COVID-19 disease. We have therefore explored ACE2 receptor mRNA 39 expression, and co-factors for Sars-CoV-2 infectivity (TMPRSS2 and furin) in bronchial brushes and 40 biopsies from people with asthma and healthy controls, and looked for relationships between 41 asthma severity, Th2-and IL-17 dependent gene signatures, and clinical demographics (age, sex). We 42 have looked at a cohort of 356 research participants from previously described studies. The only 43 significant association was a positive correlation between ACE2 and IL-17-dependent gene 44 expression, and an inverse correlation between ACE2 and Th2-cytokine-dependent gene expression. 45

These data suggest that differences in ACE2, TMPRSS2 and furin epithelial and airway gene 46 expression are unlikely to confer enhanced COVID-19 pneumonia risk in patients with asthma across 47 all treatment intensities and severity. 48

Expression of mRNA for ACE2, the Sars-CoV-2 receptor, is similar in the lower airways of healthy 51 controls and people with mild-severe asthma. Altered ACE2 expression is unlikely to confer 52 enhanced COVID-19 pneumonia risk in asthma. 53

To the Editor, 55

Coronavirus disease 2019 (COVID-19) is caused by a novel zoonotic coronavirus known as Severe 56

Acute Respiratory Syndrome Coronavirus 2 (SARS-CoV-2) and has been identified as a pandemic by 57 the World Health Organization (WHO). Several risk factors have been identified for severe COVID-19-58 associated pneumonia including increased age and the presence of co-morbidities, in particular 59 diabetes, cardiovascular disease, and tobacco smoking 1 . However, a number of reports have failed 60 to identify excess risk in patients with respiratory airway diseases such as asthma 2 . ACE2, TMPRSS2 or furin mRNA expression between people with asthma compared to healthy 90 controls (p=0.96), no significant differences in ACE2 expression between males and females, and no 91 correlation between ACE2 gene expression and age (data not shown). There were no differences in 92 ACE2, TMPRSS2 or furin gene expression between healthy volunteers and people with mild-93 moderate and severe asthma (Fig.1A-C) ). ACE2, TMPRSS2 or furin gene expression were not 94 correlated. 95

There were weak but highly significant inverse and positive correlations between ACE2 expression 96 and the expression of Th2-dependent and IL-17(Th17)-dependent epithelial gene signatures 97 respectively, defined as previously 4 (Fig,1D-E) . Similar observations were noted in bronchial 98 biopsies with no differences in ACE2 gene expression between healthy volunteers, mild to moderate 99 and severe asthmatics (p=0.43)(not shown). 100

These data would suggest that differences in ACE2, TMPRSS2 and furin epithelial and airway gene 101 expression are unlikely to confer enhanced COVID-19 pneumonia risk in patients with asthma across 102 all treatment intensities and severity. It is therefore possible that the risk of severe COVID-19 103 pneumonia is no greater than the background population risk in asthmatics in the absence of other known risk factors such as diabetes and cardiovascular disease. This would support current guidance 105 on the use of inhaled steroids and rescue prednisolone in asthmatics that experience exacerbations 106 during the COVID-19 pandemic. 107 A previous mouse model of infection demonstrated that ACE2 inhibits neutrophil infiltration and 108 lung inflammation by limiting IL-17 signaling by reducing the activity of the STAT3 pathway 9 . 109 However, our observations in bronchial brush airway epithelial cells identified a positive correlation 110 between ACE2 gene expression and a previously described IL-17-dependent gene expression 111 signature, with an inverse association with Th2 gene expression. It is possible that ACE2 protein 112 expression in the airways might not mirror the RNA expression, which is a limitation of our study. 113

Furthermore, the precise relationship between other host immunoregulatory factors that may 114 modify the risk of severe COVID-19 pneumonia and asthma, as well as corticosteroid exposure which 115 may induce Th17 immunity in asthma, have not been examined here directly. However, our data are 116 in keeping with a recent report demonstrating that in nasal brushings from children, ACE2 117 expression was inversely correlated with markers of type 2 immunity, with no influence of sex or use 118 of nasal corticosteroids 10 . In the same paper, it was shown that segmental bronchial allergen 119 challenge in adults with mild asthma led to decreases in ACE2 expression, and that IL-13 reduces 120 ACE2 expression on cultured bronchial epithelial cells. 121

In summary, these data suggest it will be important to understand further the effects of Th2 and IL-122 17-driven inflammation, and inhaled corticosteroids on airway epithelial cell ACE2 expression, and 123 the susceptibility of these cells to infection and replication by SARS-CoV2. 

Clinical course and risk factors for mortality of adult 148 inpatients with COVID-19 in Wuhan, China: a retrospective cohort study

Clinical characteristics of 140 patients 151 infected with SARS-CoV-2 in Wuhan, China

SARS-CoV-2 receptor 153 ACE2 and TMPRSS2 are primarily expressed in bronchial transient secretory cells

Th2 and Th17 156 inflammatory pathways are reciprocally regulated in asthma

Periostin is a systemic 159 biomarker of eosinophilic airway inflammation in asthmatic patients

Altered Epithelial Gene 168 Expression in Peripheral Airways of Severe Asthma

A Dynamic Variation of

Pulmonary ACE2 Is Required to Modulate Neutrophilic Inflammation in Response to Pseudomonas 172 aeruginosa Lung Infection in Mice

Asthma and Expression of the SARS-CoV-2 Receptor, ACE2