Application of System Biology to Explore the Association of Neprilysin, Angiotensin-Converting Enzyme 2 (ACE2), and Carbonic Anhydrase (CA) in Pathogenesis of SARS-CoV-2

Abstract

Background: Coronavirus disease 2019 (COVID-19) is caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) appears with common symptoms including fever, dry cough, and fatigue, as well as some less common sysmptoms such as loss of taste and smell, diarrhea, skin rashes and discoloration of fingers. COVID-19 patients may also suffer from serious symptoms including shortness of breathing, chest pressure and pain, as well as loss of daily routine habits, pointing out to a sever reduction in the quality of life. COVID-19 has afftected almost all countries, however, the United States contains the highest number of infection (> 1,595,000 cases) and deaths cases (> 95,000 deaths) in the world until May 21, 2020. Finding an influential treatment strategy against COVID-19 can be facilitated through better understanding of the virus pathogenesis and consequently interrupting the biochemical pathways that the virus may play role in human body as the current reservoir of the virus.

Results: In this study, we combined system biology and bioinformatic approaches to define the role of coexpression of angiotensin-converting enzyme 2 (ACE2), neprilysin or membrane metallo-endopeptidase (MME), and carbonic anhydrases (CAs) and their association in the pathogenesis of SARS-CoV-2. The results revealed that ACE2 as the cellular attachment site of SARS-CoV-2, neprilysin, and CAs have a great contribution together in the renin angiotensin system (RAS) and consequently in pathogenesis of SARS-CoV-2 in the vital organs such as respiratory, renal, and blood circulation systems. Any disorder in neprilysin, ACE2, and CAs can lead to increase of CO₂ concentration in blood and respiratory acidosis, induction of pulmonary edema and heart and renal failures.

Conclusions: Due to the presence of ACE2-Neprilysin-CA complex in most of vital organs and as a receptor of COVID-19, it is expected that most organs are affected by SARS-CoV-2 such as inflammation and fibrosis of lungs, which may conversely affect their vital functions, temporary or permanently, sometimes leading to death. Therefore, ACE2-Neprilysin-CA complex could be the key factor of pathogenesis of SARS-CoV-2 and may provide us useful information to find better provocative and therapeutic strategies against COVID-19.

Keywords: Acute respiratory syndrome; Angiotensin-converting enzyme 2 (ACE2); COVID-19; Carbonic anhydrases (CAs); Neprilysin; Renin angiotensin system (RAS); Respiratory acidosis; SARS-CoV-2.

Fig. 1

Coexpression of ACE2, neprilysin or MME, and CA in RAS. Red arrows are showing ACE2-Neprilysin-CA association network. The network consist of 22 proteins that two out of them are still not characterized

Fig. 2

Association of neprilysin or MME and ACE2. ACE2 is crucial in conversion of angiotensin I to Ang-(1-9) angiotsnsin II to Ang-(1-7), and angiotensin A (AngA) to alamandine. In addition, neprilysin or MME is essential in conversion of angiotensin I to Ang-(1-7) and Ang-(1-9) to angiotensin Ang-(1-7)

Fig. 3

Localization of (a) neprilysin or MME, (b) ACE2, and (c) CA VB in the human organs. THE HUMAN PROTEIN ATLAS shows the overlap of bars and association of ACE2, neprilysin, and CA in various organs including digestive, renal, respiratory, and reproductive systems