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COVID-19: Pathophysiology

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By Matthew E. Levison, MD, Adjunct Professor of Medicine, Drexel University College of Medicine

1/21/2021

Matthew Levison, MD

SARS-CoV-2 Host Cell Receptor

 

Angiotensin-converting enzyme 2 (ACE2), first identified in 2000, is an enzyme attached to the surface of host cells and is the entry point for SARS-CoV-2. ACE2 is widely distributed throughout the body, being expressed on nasal epithelial cells, lung alveolar epithelial cells, small intestinal enterocytes, arterial and venous endothelial cells, and arterial smooth muscle cells in many organs studied. In the kidneys, ACE2 is expressed in the apical brush borders of the proximal tubules, as well as glomerular podocytes; but not in endothelial cells (1).

 

ACE2 regulates the renin-angiotensin system by catalyzing the hydrolysis of the octapeptide angiotensin II (AngII, a vasoconstrictor) to the heptapeptide angiotensin 1–7 (Ang1-7, a vasodilator). Ang 1-7 also opposes Ang II’s stimulation of the production of proinflammatory cytokines, such as IL-6. ACE2 has been shown to exhibit a protective function in the lung, cardiovascular system, and other organs, and has been evaluated in clinical trials for the treatment of acute respiratory distress syndrome. The consequent depletion of ACE2 following host cell infection leaves Ang II’s pro-inflammatory stimulation and consequent injury to the lung and other organs unopposed (2).

 

After being primed by the serine protease TMPRSS2, the SARS-CoV-2 spike protein binds to ACE2, followed by the virus’ entry into the host cell. Anti-ACE-2 antibodies and TMPRSS2 inhibitors can prevent SARS-CoV-2 binding to this receptor and its entry into host cells. The wide distribution of ACE2 receptors throughout the body likely explains the multiorgan effects in COVID-19.

Genetic variants in the binding site for the SARS-CoV-2 spike-protein and variation in the level of expression and expression pattern of ACE2 in different tissues may provide a genetic basis for differences in host susceptibility, symptoms, and outcome of SARS-CoV-2 infection (3, 4). Also, ACE2 expression has to been found to vary by age; in a study involving patients with asthma, expression of ACE2 by nasal epithelium was found to be less in younger children (4 to 9 years old) than in older children and people aged 10 to 60 years, and ACE2 expression, after adjusting for sex and asthma, was higher with each subsequent age group, ie, older children (10 to 17 years old), young adults (18 to 24 years old), and adults ≥ 25 years old (5). The lower ACE2 expression in young children relative to adults may help explain why COVID-19 is less prevalent and clinical manifestations are less severe in young children (6), and their frequency of transmission is less (7).

 

 

References

 

1. Su H, Yang M, Wan C, et al: Renal histopathological analysis of 26 postmortem findings of patients with COVID-19 in China. Kidney International 98(1):P219-227, 2020. https://www.kidney-international.org/article/S0085-2538(20)30369-0/fulltext

 

2. Liu M, Shi P, Sumners C: Direct anti-inflammatory effects of angiotensin-(1-7) on microglia. Journal of Neurochemistry 136:163-171, 2016. https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4688174/

 

3. Stawiski E, Diwanji D, Suryamohan K, et al: Human ACE2 receptor polymorphisms predict SARS-CoV-2 susceptibility. [PREPRINT] bioRxiv April 10, 2020 https://www.biorxiv.org/content/10.1101/2020.04.07.024752v1

 

4. Cao Y, Li L, Feng Z, et al: Comparative genetic analysis of the novel coronavirus (2019-nCoV/SARS-CoV-2) receptor ACE2 in different populations. Cell Discovery 6, 11, 2020. February 24, 2020. https://www.nature.com/articles/s41421-020-0147-1

 

5. Bunyavanich S, Do A, Vicencio A: Nasal gene expression of angiotensin-converting enzyme 2 in children and adults. JAMA 323(23):2427–2429, 2020. doi:10.1001/jama.2020.8707https://jamanetwork.com/journals/jama/fullarticle/2766524

 

6. Dong Y, Mo X, Hu Y, et al: Epidemiology of COVID-19 among children in China. Pediatrics https://pediatrics.aappublications.org/content/145/6/e20200702

 

7. Park YJ, Choe YJ, Park O, et al: Contact tracing during coronavirus disease outbreak, South Korea 2020. Emerging Infectious Diseases October 2020 [early release] July 16, 2020. Accessed July 23, 2020 https://wwwnc.cdc.gov/eid/article/26/10/20-1315-t2

 

 

 

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