COVID-19–related Genes in Sputum Cells in Asthma. Relationship to Demographic Features and Corticosteroids

Abstract

Background: Coronavirus disease 2019 is caused by SARS-coronavirus 2 (SARS-CoV-2). Angiotensin converting enzyme 2 (ACE2) and transmembrane protease serine 2 (TMPRSS2) mediate viral infection of host cells. We reasoned that differences in ACE2 or TMPRSS2 gene expression in sputum cells among asthma patients may identify subgroups at risk for COVID19 morbidity. Methods:We analyzed gene expression for ACE2 and TMPRSS2, and for intercellular adhesion molecule 1 (ICAM-1)(rhinovirus receptor as a comparator), in sputum cells from 330 participants in the Severe Asthma Research Program-3 and 79 healthy controls.Results: Gene expression of ACE2 was lower than TMPRSS2, and expression levels of both genes was similar in asthma and health. Among asthma patients, male gender, African Americans race, and history of diabetes mellitus, was associated with higher expression of ACE2 and TMPRSS2. Use of inhaled corticosteroids (ICS) was associated with lower expression of ACE2 and TMPRSS2, but treatment with triamcinolone acetonide (TA) did not decrease expression of either gene. These findings differed from those for ICAM-1, where gene expression was increased in asthma and less consistent differences were observed related to gender, race, and use of ICS. Conclusion:Higher expression of ACE2 and TMPRSS2 in males, African Americans, and patients with diabetes mellitus provides rationale for monitoring these asthma subgroups for poor COVID19 outcomes. The lower expression of ACE2 and TMPRSS2 with ICS use warrants prospective study of ICS use as a predictor of decreased susceptibility to SARS-CoV-2 infection and decreased COVID19 morbidity. the participant level with restricted maximum likelihood models. P-values <0.05 were considered statistically significant. RESULTS SubjectsThe demographic and clinical features of the asthma patients and healthy controls are shown in Table 1. Gene expression for SARS-Cov-2-and HRV-related genes in induced sputum cells from asthma patients and healthy controlsIn induced sputum cells collected at the baseline visit, the expression levels of ACE2 were lower than the expression levels of TMPRSS2, and some sputum samples had undetectable ACE2 ( Figure 1A). The expression of ACE2 and TMPRSS2 did not differ significantly in health and in asthma ( Figure 1A,B). In contrast to the SARS-Co-V2related genes, gene expression of ICAM1 was higher in asthma than in health ( Figure 1C). The expression of ACE2 was strongly associated with the expression of TMPRSS2 in the healthy control subgroup (Figure 2A) and the asthma subgroup ( Figure 2B), suggesting that these genes are expressed in similar cells(18). Relationship between clinical and demographic variables and expression levels of SARS-Cov-2-and HRV-related genes in asthma patientsHere we analyzed gene expression data in the induced sputum samples collected at the baseline visit 2 and the follow up visits 4 (year 1) and 6 (year 3). The total number was 556 samples from 330 asthma subjects. ACE2 and TMPRSS2 expression levels increased slightly with age, bu...

Inhaled corticosteroids downregulate the SARS-CoV-2 receptor ACE2 in COPD through suppression of type I interferon

“…There were no significant differences between these groups in terms of age, disease severity, smoking status or other comorbidities known to affect ACE2 expression and/or associated with increased risk of COVID-19 ( Table 1). Sputum cell ACE2 mRNA expression was detectable in 22/36 COPD subjects (61.1%) and, consistent with prior observations in asthma (17), significantly reduced in ICS users compared to nonusers (Fig 1a). Sputum cell expression of the serine protease TMPRSS2 that is used by SARS-CoV-2 for mucosal entry (13) was detectable in all subjects with no significant difference observed between ICS users and non-users (Fig 1b).…”

“…ACE2 is expressed primarily in the nasal goblet cells and type II pneumocytes within the respiratory tract (30) and is upregulated in subject groups known to be associated with increased disease severity including elderly individuals (31) and patients with diabetes (17), indicating that it may play a clinically important role in governing susceptibility to virus acquisition and/or development of severe disease in at-risk groups. ACE2 expression has similarly been shown to be increased in COPD: using combined transcriptomic and immunohistochemical analyses, Leung et al recently demonstrated that epithelial ACE2 expression is increased in bronchial brushings/tissue samples from COPD subjects versus healthy controls (32), effects also previously shown in cigarette smoke exposure animal models (33).…”

“…Currently, a direct causal link between ACE2 and increased susceptibility to acquisition of SARS-CoV-2 or subsequent severity has not been proven and we cannot conclude unequivocally that downregulation of ACE2 by ICS is an effect that would confer protection clinically. In asthma, a disease where ICS are more commonly prescribed than in COPD, ACE2 expression is reduced compared to healthy subjects (15) and also further attenuated in ICS users (17). In contrast to COPD, asthma has not been shown to be associated with increased COVID-19 mortality (5) and the more widespread use of ICS with associated suppression of ACE2 could theoretically be one factor driving this.…”

“…Increased epithelial ACE2 expression has been recently reported in smokers and subjects with COPD (14) and is postulated to be a factor predisposing these individuals to adverse outcome from COVID-19. Conversely, ACE2 is downregulated in asthma (15), an effect that may be due to suppressive effects of type 2 cytokines (16) or related to ICS use (17).…”

Repositioning of ligands that target spike glycoprotein as potential drugs against SARS-CoV-2

“…The use of Betamehasone and Dexamehasone effect on hinge site blockage not been explored, the two corticosteroids have the same molecular weight and high structural similarity (the only difference is the orientation of the methyl group on carbon 16) so which could have similar effects. Use of inhaled corticosteroids had been associated with lower expression of ACE2 and TMPRSS2, but treatment with Triamcinolone Acetonide did not decrease expression of either gene [19]. On the other hand, the use of Atazanavir (protease inhibitor) has been reported in computer studies with inhibitory potency activity with Kd of 94.94 nM against the SARS-CoV-2 3C-like protease inhibitor [2].…”