Expression of SARS-CoV-2 receptor ACE2 and coincident host response signature varies by asthma inflammatory phenotype

Abstract

Background: More than 300 million people carry a diagnosis of asthma, with data to suggest that they are at a higher risk for infection or adverse outcomes from severe acute respiratory syndrome coronavirus 2. Asthma is remarkably heterogeneous, and it is currently unclear how patient-intrinsic factors may relate to coronavirus disease 2019. Objective: We sought to identify and characterize subsets of patients with asthma at increased risk for severe acute respiratory syndrome coronavirus 2 infection. Methods: Participants from 2 large asthma cohorts were stratified using clinically relevant parameters to identify factors related to angiotensin-converting enzyme-2 (ACE2) expression within bronchial epithelium. ACE-2-correlated gene signatures were used to interrogate publicly available databases to identify upstream signaling events and novel therapeutic targets. Results: Stratifying by type 2 inflammatory biomarkers, we identified subjects who demonstrated low peripheral blood eosinophils accompanied by increased expression of the severe acute respiratory syndrome coronavirus 2 receptor ACE2 in bronchial epithelium. Genes highly correlated with ACE2 overlapped with type 1 and 2 IFN signatures, normally induced by viral infections. T-cell recruitment and activation within bronchoalveolar lavage cells of ACE2-high subjects was reciprocally increased. These patients demonstrated characteristics corresponding to risk factors for severe coronavirus disease 2019, including male sex, history of hypertension, low peripheral blood, and elevated bronchoalveolar lavage lymphocytes. Conclusions: ACE2 expression is linked to upregulation of viral response genes in a subset of type 2-low patients with asthma with characteristics resembling known risk factors for severe coronavirus disease 2019. Therapies targeting the IFN family and T-cell-activating factors may therefore be of benefit in a subset of patients.

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

“…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 .…”

“…It has been reported that patients with asthma have reduced susceptibility to SARS-CoV-2, and that asthma symptoms are not exacerbated by SARS-CoV-2 infection [43][44][45] . However, it has been suggested that a subset of asthma patients (Type-2 low asthmatics) who are more at risk of SARS-CoV-2 show higher ACE2 expression in bronchial epithelium, associated with upregulation of viral response genes 46 .…”

SARS-CoV-2 Infections Among Children in the Biospecimens from Respiratory Virus-Exposed Kids (BRAVE Kids) Study

“… 24 These observations have led to speculation that asthma may lower SARS-CoV-2 susceptibility, or alternatively protect from severe COVID-19, by promoting a Th2-dominant immune response or through reduced expression of the SARS-CoV-2 receptor (ACE2). 25 …”

Chronic lung diseases are associated with gene expression programs favoring SARS-CoV-2 entry and severity

“…To our knowledge, publications investigating baseline expression of these SARS-CoV-2 entry factors in lung disease have been limited to asthma and COPD with variable results. For example, studies in asthma patients showed elevated expression of ACE2, TMPRSS2 and FURIN in patients with severe but not mild-moderate asthma 49,69 . Leung et al performed bulk RNAseq and immunohistochemical staining on bronchial epithelial cells and showed signi cantly elevated expression levels of ACE2 and ACE2 protein in the small airways of COPD patients compared to control 70 .…”