Angiotensin-converting enzyme 2 in peripheral lung club cells modulates the susceptibility to SARS-CoV-2 in chronic obstructive pulmonary disease

Abstract

Accumulating evidence has confirmed that chronic obstructive pulmonary disease (COPD) is a risk factor for development of severe pathological changes in the peripheral lungs of patients with COVID-19. However, the underlying molecular mechanisms remain unclear. Because bronchiolar club cells are crucial for maintaining small airway homeostasis, we sought to explore whether the altered susceptibility to SARS-CoV-2 infection of the club cells might have contributed to the severe COVID-19 pneumonia in COPD patients. Our investigation on the quantity and distribution patterns of angiotensin-converting enzyme 2 (ACE2) in airway epithelium via immunofluorescence staining revealed that the mean fluorescence intensity of the ACE2-positive epithelial cells was significantly higher in club cells than those in other epithelial cells (including ciliated cells, basal cells, goblet cells, neuroendocrine cells, and alveolar type 2 cells). Compared with nonsmokers, the median percentage of club cells in bronchiolar epithelium and ACE2-positive club cells was significantly higher in COPD patients. In vitro, SARS-CoV-2 infection (at a multiplicity of infection of 1.0) of primary small airway epithelial cells, cultured on air-liquid interface, confirmed a higher percentage of infected ACE2-positive club cells in COPD patients than in nonsmokers. Our findings have indicated the role of club cells in modulating the pathogenesis of SARS-CoV-2-related severe pneumonia and the poor clinical outcomes, which may help physicians to formulate a novel therapeutic strategy for COVID-19 patients with coexisting COPD.

Lung Remodeling Regions in Long-Term Coronavirus Disease 2019 Feature Basal Epithelial Cell Reprogramming

“…In a related point, AT2 cells were not a primary site for viral receptor ACE-2 expression using mAb and pAb detection to account for variation in epitope recognition. This result is similar to expression on a relatively rare subset of AT2 cells in other studies of human lung tissue 17 , 37 , 38 , 39 . These data also highlight the distinctive nature of the basal-epithelial versus AT2 cell lineage in the setting of respiratory viral infection.…”

LY6E protects mice from pathogenic effects of murine coronavirus and SARS-CoV-2

“…At the tissue level, Ly6e knockout mice exhibited a robust antiviral interferon response after SARS-CoV-2 infection that paralleled that of wildtype mice, but also expressed fewer secretory cell genes when compared to uninfected Ly6e knockout mice or infected wildtype mice (Figure 5, S4). SARS-CoV-2 has been previously shown to exhibit tropism for lower respiratory tract secretory club cells (Salahudeen et al 2020; Ravindra et al 2021; Fiege et al 2021; Peng et al 2022), which was associated with subsequent loss of the secretory club cell marker, Scgb1a1 , in a mouse-adapted SARS-CoV-2 model (Leist et al 2020). Infection of Ly6e knockout mice with a natural SARS-CoV-2 variant of concern may therefore be a useful tool for understanding how increased susceptibility of secretory cells results in clinical disease.…”

[Retracted] The Efficacy and Safety of Budesonide/Glycopyrronium/Formoterol in the Treatment of COPD in the Elderly

“…The occurrence and development of these diseases are closely related to aging. Some changes in the structure and molecular phenotype of aging may participate in this process [ 39 ]. In addition, at present, the treatment of pulmonary fibrosis and chronic obstructive pulmonary disease mainly includes nondrug management (pulmonary rehabilitation, oxygen supplement, and surgical treatment) and drug management (glucocorticoids, immunosuppressants, bronchodilators, and targeted drugs) [ 38 ].…”