Assessing ACE2 expression patterns in lung tissues in the pathogenesis of COVID-19

Abstract

It has been reported that SARS-CoV-2 may use ACE2 as a receptor to gain entry into human cells, in a way similar to that of SARS-CoV. Analyzing the distribution and expression level of ACE2 may therefore help reveal underlying mechanisms of viral susceptibility and post-infection modulation. In this study, we utilized previously uploaded information on ACE2 expression in various conditions including SARS-CoA to evaluate the role of ACE2 in SARS-CoV and extrapolate that to COVID-19. We found that the expression of ACE2 in healthy populations and patients with underlying diseases was not significantly different. However, based on the elevated expression of ACE2 in cigarette smokers, we speculate that long-term smoking may be a risk factor for COVID-19. Analysis of ACE2 in SARS-CoV infected cells suggests that ACE2 is not only a receptor but is also involved in post-infection regulation, including immune response, cytokine secretion, and viral genome replication. Moreover, we constructed Protein-protein interaction (PPI) networks and identified hub genes in viral activity and cytokine secretion. Our findings may help clinicians and researchers gain more insight into the pathogenesis of SARS-CoV-2 and design therapeutic strategies for COVID-19.

Keywords: 2019-nCoV; ACE2; COVID-19; Immune response; Protein-protein interactions; SARS-CoV-2; Susceptibility.

Fig. 1

Expression of ACE2 in lung tissues and epithelial cells. A. Expression of ACE2 in lung tissue from healthy smokers, moderate COPD patients and non-smokers. B. Expression of ACE2 in bronchoalveolar lavage samples from COPD patients and healthy volunteers. C. Expression of ACE2 in asthma patients. D. Expression of ACE2 in small airway epithelial cells in smokers (S) and non-smokers (NS). E. Expression of ACE2 after ASE. F. Expression of ACE2 in SARS-CoV infected bronchial cells. ASE = acute smoke exposure.

Fig. 2

Functional analysis of ACE2 revealing related biological processes. A. GSEA analysis showing the related biological processes of ACE2 in healthy non-smokers. B. Immune cell infiltration in healthy population. C. GSVA score of key processes showing time-dependent alterations. D. Immune cell infiltration in SARS-CoV infected cells.

Fig. 3

PPI network. A: PPI network of viral replication-related proteins. B: PPI network of cytokine secretion-related proteins.

Fig. 4

A schematic model of SARS-CoV-2 infection. SARS-CoV-2 uses ACE2 as a cellular entry receptor in airway epithelial cells. At the same time, the expression of ACE2 is increased by the infection. Furthermore, the increased expression of ACE2 affected RPS3 and SRC, the two hub genes involved in viral replication and inflammatory responses.

Fig. 5

Effect of ACE2 and ARBs on SARS-CoV-1 or SARS-CoV-2 infection. This illustrates a proposed mechanism of the effects of ACE2 in COVID-19 infection. SARS-COV-2 virus uses the ACE2 receptor to gain entry into the cell, leading to the increase in proinflammatory cytokines and the development of cytokine storm, as well as increased viral replication (see Fig. 4). TMPRSS2 assists in S protein priming. ARBs may potentially increase the expression of ACE2, leading increased binding of SARS-CoV-2 and greater proinflammatory cytokine production. SARS-CoV-2 may at the same time downregulate ACE2, which leads to an increase in angiotensin 2 mediated lung injury. The negative regulatory activity of ACE2 is reduced by SARS-CoV-2 and leads to worsening severity of illness.