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

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.

Implications of preexisting asthma on COVID-19 pathogenesis

“…However, ACE2 expression negatively and positively correlated with Th2- and Th17-dependent epithelial signatures, respectively. Contrasting results were obtained from a similar study in which the gene expression of ACE2, TMPRSS2 , and furin was elevated in severe asthma, particularly the neutrophilic phenotype, in comparison with mild-to-moderate asthma and healthy controls ( 51 ). Thus, there is a possibility that the neutrophilic phenotype in patients with severe asthma may place them at increased risk of COVID-19.…”

Molecular and Biological Mechanisms Underlying Gender Differences in COVID-19 Severity and Mortality

“…Gender disparity in furin expression has been previously demonstrated in asthmatic patients. Specifically, bronchial cell samples obtained from asthmatic patients revealed that furin is positively associated with the male gender and this was speculated as a possible factor contributing to COVID-19 severity (96). Further analysis of genetic variations at the FCS and any associated gender differences may offer insight to the more pronounced COVID-19 severity and mortality in males.…”

Association of endopeptidases, involved in SARS‐CoV‐2 infection, with microbial aggravation in sputum of severe asthma

“…9 Sputum transcriptomics, SomaScan ® proteomics, and metagenomics were assayed as described previously. 5,6 Gene set variation analysis (GSVA) was performed to obtain the enrichment score (ES) of the endopeptidase genes (TMPRSS2 and furin). Spearman correlation coefficients were computed between endopeptidases ES and sputum inflammatory markers and metagenomics α-diversity measures.…”

“…3 The heterogeneous inflammatory nature of asthma raises the possibility that the type of asthmatic inflammation might determine the outcome of SARS-CoV-2 infection in asthma. Type 2 (T2) inflammatory markers have been associated with decreased ACE2 expression in asthma 4,5 that could underlie the reduced risk of SARS-CoV-2 infection in asthmatics. In contrast, non-T2 asthma, particularly neutrophilic asthma, has been associated with higher ACE2 and endopeptidases (TMPRSS2 and furin) expression as compared with the T2-high phenotype 4,5 that might imply a worse outcome with COVID-19 infection.…”

“…Severe nonsmoking (n = 61) and smoking (n = 23) asthmatics showed the highest median expression ES of endopeptidase as compared to mild-moderate asthmatics (n = 20) and healthy controls (n = 16) (Figure 1A), consistent with previous findings. 5 The endopeptidases ESs were significantly correlated with sputum neutrophil absolute counts (r s = 0.55, p = 7.7 × 10 −11 ) and percentages (r s = 0.58, p = 2.4 × 10 −12 ), which suggests that the endopeptidases were neu- The endopeptidase-high group (mean age = 50.9 ± 13.2, 53.3% females) had higher sputum neutrophils (Figure 1B), with no differences in sputum eosinophils (Figure 1C), and exhibited reduced bacterial α-diversity measures as compared with the endopeptidase-low group (mean age = 48.2 ± 14.6 years, 53.3% females) (Figure 1D). In addition, the endopeptidase-high group had a higher abundance of pathogenic bacteria, such as Moraxella catarrhalis and Haemophilus influenzae, displaying a pattern of pathogenic bacterial aggravation compared with endopeptidase-low group (Figure 2A), while the latter had a higher abundance of commensal bacteria, such as Rothia and Prevotella species.…”