Dysbalance of ACE2 levels – a possible cause for severe COVID‐19 outcome in COPD

Abstract

Severe acute respiratory syndrome coronavirus 2 (SARS‐CoV‐2) poses a serious threat to healthcare systems worldwide. Binding of the virus to angiotensin‐converting enzyme 2 (ACE2) is an important step in the infection mechanism. However, it is unknown if ACE2 expression in patients with chronic lung diseases (CLDs), such as chronic obstructive pulmonary disease (COPD), idiopathic pulmonary arterial hypertension (IPAH), or pulmonary fibrosis (PF), is changed as compared to controls. We used lung samples from patients with COPD ( n = 28), IPAH ( n = 10), and PF ( n = 10) as well as healthy control donor ( n = 10) tissue samples to investigate the expression of ACE2 and related cofactors that might influence the course of SARS‐CoV‐2 infection. Expression levels of the ACE2 receptor, the putative receptor CD147/ BSG , and the viral entry cofactors TMPRSS2 (transmembrane serine protease 2), EZR , and FURIN were determined by quantitative PCR and in open‐access RNA sequencing datasets. Immunohistochemical and single‐cell RNA sequencing (scRNAseq) analyses were used for localization and coexpression, respectively. Soluble ACE2 (sACE2) plasma levels were analyzed by enzyme‐linked immunosorbent assay. In COPD as compared to donor, IPAH, and PF lung tissue, gene expression of ACE2 , TMPRSS2 , and EZR was significantly elevated, but circulating sACE2 levels were significantly reduced in COPD and PF plasma compared to healthy control and IPAH plasma samples. Lung tissue expressions of FURIN and CD147/ BSG were downregulated in COPD. None of these changes were associated with changes in pulmonary hemodynamics. Histological analysis revealed coexpression of ACE2, TMPRSS2, and Ezrin in bronchial regions and epithelial cells. This was confirmed by scRNAseq analysis. There were no significant expression changes of the analyzed molecules in the lung tissue of IPAH and idiopathic PF as compared to control. In conclusion, we reveal increased ACE2 and TMPRSS2 expression in lung tissue with a concomitant decrease of protective sACE2 in COPD patients. These changes represent the possible risk factors for an increased susceptibility of COPD patients to SARS‐CoV‐2 infection.

Decreased serum levels of angiotensin converting enzyme (ACE)2 and enhanced cytokine levels with severity of COVID-19: normalisation upon disease recovery

“…In addition, high plasma sACE2 levels may be a predictor of COVID-19 severity and outcomes as well as a risk factor for hypertension, pre-existing heart disease and pre-existing kidney disease [ 37 ]. In contrast, in lung diseases circulating sACE2 levels were significantly reduced in COPD and pulmonary fibrosis (PF) compared to healthy control [ 38 ]. sACE2 levels may merely reflect the inflammatory state which is indicated by serum CRP levels.…”

Differential Co-Expression Network Analysis Reveals Key Hub-High Traffic Genes as Potential Therapeutic Targets for COVID-19 Pandemic

“…Other critical hub-high traffic genes in the blue module included EP300 ( 146 , 147 ), CDK1 ( 4 , 148 ), VEGFA ( 149 – 151 ), CTNNB1 ( 151 , 152 ), IL10 ( 9 , 153 – 155 ), SOCS1 , SOCS3 ( 156 ), SIRT1 ( 157 , 158 ), TFRC ( 159 – 161 ), HSP90AB1 ( 162 ), CYCS ( 163 ), EZR ( 164 ), TNFAIP3 , ICAM1 ( 10 ), and PIK3R1 ( 139 ) as well as TFs such as ATF4 ( 165 ), ATF3 ( 166 , 167 ), and BCL6 ( 152 ) which have important roles in pathogenesis of SARS-CoV-2, and some of which are potential therapeutic targets. For instance, SOCS1 / 3 antagonists may be prophylactic or therapeutic against the COVID-19 pandemic ( 156 ).…”

COVID 19, emphysema, and secondary pulmonary fibrosis: About a case report

“…Chronic exposure to cigarette smoke alters the molecular expression of the angiotensin-converting enzyme 2 (ACE2) receptor, which is primarily responsible for the binding and entry of SARS-CoV-2 to the cell and the cofactor transmembrane serine protease 2. [10] Moreover, it compromises host immunity through several mechanisms, involving both innate and adaptive immune responses. Strikingly, cigarette smoke exposure increases the number of alveolar macrophages in COPD; however, their phagocytic capacity, expression of antiviral mediators, and clearance of apoptotic cells is reduced.…”