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. 2021 Jan 7;22(1):10.
doi: 10.1186/s12931-020-01605-8.

Sputum ACE2, TMPRSS2 and FURIN gene expression in severe neutrophilic asthma

Nazanin Zounemat Kermani #  1   2 , Woo-Jung Song #  2   3 , Yusef Badi  1   2 , Ali Versi  1   2 , Yike Guo  1 , Kai Sun  1 , Pank Bhavsar  2 , Peter Howarth  4   5 , Sven-Erik Dahlen  6 , Peter J Sterk  7 , Ratko Djukanovic  4   5 , Ian M Adcock  1   2 , Kian Fan Chung  8   9 ; U-BIOPRED Consortium
Collaborators, Affiliations

Sputum ACE2, TMPRSS2 and FURIN gene expression in severe neutrophilic asthma

Nazanin Zounemat Kermani et al. Respir Res. .

Erratum in

Abstract

Background: Patients with severe asthma may have a greater risk of dying from COVID-19 disease. Angiotensin converting enzyme-2 (ACE2) and the enzyme proteases, transmembrane protease serine 2 (TMPRSS2) and FURIN, are needed for viral attachment and invasion into host cells.

Methods: We examined microarray mRNA expression of ACE2, TMPRSS2 and FURIN in sputum, bronchial brushing and bronchial biopsies of the European U-BIOPRED cohort. Clinical parameters and molecular phenotypes, including asthma severity, sputum inflammatory cells, lung functions, oral corticosteroid (OCS) use, and transcriptomic-associated clusters, were examined in relation to gene expression levels.

Results: ACE2 levels were significantly increased in sputum of severe asthma compared to mild-moderate asthma. In multivariate analyses, sputum ACE2 levels were positively associated with OCS use and male gender. Sputum FURIN levels were significantly related to neutrophils (%) and the presence of severe asthma. In bronchial brushing samples, TMPRSS2 levels were positively associated with male gender and body mass index, whereas FURIN levels with male gender and blood neutrophils. In bronchial biopsies, TMPRSS2 levels were positively related to blood neutrophils. The neutrophilic molecular phenotype characterised by high inflammasome activation expressed significantly higher FURIN levels in sputum than the eosinophilic Type 2-high or the pauci-granulocytic oxidative phosphorylation phenotypes.

Conclusion: Levels of ACE2 and FURIN may differ by clinical or molecular phenotypes of asthma. Sputum FURIN expression levels were strongly associated with neutrophilic inflammation and with inflammasome activation. This might indicate the potential for a greater morbidity and mortality outcome from SARS-CoV-2 infection in neutrophilic severe asthma.

Keywords: ACE2; FURIN; Neutrophil; Severe asthma; TMPRSS2.

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Conflict of interest statement

Dr Djukanovic reports receiving fees for lectures at symposia organised by Novartis, AstraZeneca and TEVA, consultation for TEVA and Novartis as member of advisory boards, and participation in a scientific discussion about asthma organised by GlaxoSmithKline. He is a co-founder and current consultant, and has shares in Synairgen, a University of Southampton spin out company. Dr. Sterk has nothing to disclose. Dr. Sterk reports grants from public–private funding by the Innovative Medicines Initiative (IMI) covered by the European Union (EU) and the European Federation of Pharmaceutical Industries and Associations (EFPIA), during the conduct of the study. Dr Chung has received honoraria for participating in Advisory Board meetings of GSK, AZ, Roche, Novartis, Merck, BI, TEVA and Shionogi regarding treatments for asthma, chronic obstructive pulmonary disease and chronic cough and has also been renumerated for speaking engagements. Dr. Dahlén reports personal fees from AZ, Cayman Chemical, GSK, Novartis, Sanofi, Regeneron, TEVA, outside the submitted work. Mr Versi, Dr Kermani, Dr Song, Mr Badi, Dr Guo, Dr Sun, Dr Bhavsar, Dr Howarth and Dr Adcock have nothing to disclose.

Figures

Fig. 1
Fig. 1
Comparison of ACE2, TMPRSS2 and FURIN gene expression levels (box-and-whisker plots showing median and interquartile range) between healthy volunteers and asthmatics in different airway compartments. ACE2 (a, d, g), TMPRSS2 (b, e, h) and FURIN (c, f, i) mRNA expression was assessed in sputum (a–c), bronchial brushings (d–f), and bronchial biopsies (g–i) compartments from healthy volunteers and asthmatics of different severity. SA severe asthmatics, MMA mild-to-moderate asthmatics, HV healthy volunteers, ns not significant (p > 0.05). P values were determined by one-way ANOVA and Tukey’s multiple comparison tests
Fig. 2
Fig. 2
Forest plots showing associations between gene expression of ACE2, TMPRRS2 and FURIN, and baseline characteristics in a sputum, b bronchial brushings and c bronchial biopsies of asthmatics. Regression coefficients (95% confidence intervals) and p values were determined using multivariate linear regression tests for each gene expression level (as a dependent variable) and baseline parameters including age, gender, and those showing p values < 0.05 in univariate regression tests (shown in Table 1) as independent variables. All independent variables included in each multivariate model are presented. Gene expression levels and inflammatory cell counts (in sputum and blood) were log-transformed to normalize the distribution. Statically significant parameters (p < 0.05) are indicated with red color in symbol. FEV1 forced expiratory volume in the first second, OCS oral corticosteroid use, post-BD post bronchodilator
Fig. 3
Fig. 3
Scatter dot plots showing correlations between sputum FURIN gene expression levels and a neutrophils (%), b enrichment score (ES) of neutrophil activation gene signature and c ES of IL6-trans-signaling (IL6-TS) gene signature in sputum of asthmatics (n = 104). Correlation coefficients and p values were determined by Spearman’s tests
Fig. 4
Fig. 4
Comparison of a ACE2, b TMPRSS2 and c FURIN gene expression levels across transcriptomic-associated clusters (TACs) in sputum samples. Data shown as box-and-whisker plots showing median and interquartile range. ns not significant (p > 0.05). P values were determined by one-way ANOVA and Tukey’s multiple comparison tests
See this image and copyright information in PMC

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