Abstract
SARS-CoV-2, the pathogenic agent of COVID-19, employs angiotensin converting enzyme-2 (ACE2) as its cell entry receptor. Clinical data reveal that in severe COVID-19, SARS-CoV-2 infects the lung, leading to a frequently lethal triad of respiratory insufficiency, acute cardiovascular failure, and coagulopathy. Physiologically, ACE2 plays a role in the regulation of three systems that could potentially be involved in the pathogenesis of severe COVID-19: the kinin–kallikrein system, resulting in acute lung inflammatory edema; the renin–angiotensin system, promoting cardiovascular instability; and the coagulation system, leading to thromboembolism. Here we assembled a healthy human lung cell atlas meta-analysis with ~ 130,000 public single-cell transcriptomes and show that key elements of the bradykinin, angiotensin and coagulation systems are co-expressed with ACE2 in alveolar cells and associated with their differentiation dynamics, which could explain how changes in ACE2 promoted by SARS-CoV-2 cell entry result in the development of the three most severe clinical components of COVID-19.
Highlights
SARS-CoV-2, the pathogenic agent of COVID-19, employs angiotensin converting enzyme-2 (ACE2) as its cell entry receptor
A protein–protein interaction network (Fig. 1C) revealed that ACE2 interacts closely with proteins that belong to the KKS; kininogen (KNG1), the substrate for bradykinin synthesis, and kallikrein (KLKB1), the enzyme that catalyzes this conversion
We investigated the expression of ACE2 and show that it is restricted to alveolar cells and fibroblasts, being practically absent from other cell clusters (Fig. 2C)
Summary
SARS-CoV-2, the pathogenic agent of COVID-19, employs angiotensin converting enzyme-2 (ACE2) as its cell entry receptor. Upon SARS-CoV-2 binding, ACE2 is internalized to endosomes, leading to a subcellular location shift that could alter its capacity to physiologically regulate the KKS, RAS and CS18–22 This could simultaneously impact the highly lethal COVID-19 triad: lung inflammation, cardiovascular failure, and coagulopathy. Despite the fact that ACE2 is expressed in several organs and tissues, both clinical and experimental evidence shows that SARSCoV-2 promotes most of its pathological actions by initially infecting cells of the upper respiratory tract and, subsequently, alveolar cells in the lung[23,24,25] It is currently unknown if lung cells expressing ACE2 are equipped with proteins that belong to the KKS, RAS and CS, which could potentially explain a cell-autonomous system that is disturbed by SARS-CoV-2 infection, leading to abnormal regulation of all three systems. We show that transcripts encoding for key elements of all three systems are highly co-expressed with ACE2 in alveolar cells
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