ACE2: its diverse functions, relationship with SARS-CoV-2, and the implications for COVID-19 disease sequelae

In a recent study published in the Cell, researchers assessed the role of angiotensin-converting enzyme 2 (ACE2) in the coronavirus disease 2019 (COVID-19) pandemic.

Background

ACE2 is one of the most commonly therapeutically targeted molecules in biomedicine due to the COVID-19 pandemic. ACE2 modifies the equilibrium of the peptide cascade as an enzyme, and as a chaperone, it regulates the intestinal uptake of amino acids. Current studies concentrate on regulating the ACE2 axis to functionally and structurally curb SARS-CoV-2 infections and protect against multi-organ damage. Therefore, knowing the precise function of ACE2 in COVID-19 is essential for developing targeted and effective treatments.

ACE2 as a crucial SARS-CoV-2 entry receptor

After SARS-CoV-2 was discovered as the causal agent of COVID-19, cell culture experiments revealed that ACE2 serves as its entry receptor. Studies further discovered that both in vitro and in vivo, ACE2 is the essential receptor for both SARS-CoV and SARS-CoV-2 infections.

SARS-CoV and SARS-CoV-2 are betacoronaviruses, which most likely originated in bats. The spike protein-encoding S gene is the most common locus for recombination to increase receptor binding affinities for ACE2, indicating that evolutionary adaptation of the SARS-CoV-2 receptor-binding domain (RBD) is essential for cross-species transmission.

Indicative of ACE2's fundamental physiological functions, ACE2 orthologs are largely conserved across all vertebrate species and have even been detected in insects. Evolutionary interaction between ACE2 amino acid residues that interact with the RBDs of SARS-CoV and SARS-CoV-2 accounts for the broad host tropism, promoting zoonotic transmission and viral development of SARS-CoV-2.

All SARS-related coronaviruses attach to ACE2 with variable affinities, even though certain sarbecoviruses clades have been found to have lost the ability to interact with ACE2 due to deletions and substitutions in the ACE2-binding region. At the population level in humans, ACE2 variants are prevalent but incredibly rare; however, structural and functional analyses reveal that certain human ACE2 variants may promote or inhibit spike protein binding.

SARS-CoV-2 infections facilitated by ACE2 distribution

The tropism and variety of extrapulmonary symptoms of SARS-CoV-2 are reliant on ACE2 tissue expression and distribution. Specific to the infectious process and primary viral transmission, ACE2 expression decreases from the nasal epithelium to the lower respiratory tract, correlating with viral infectivity patterns.

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Expression of ACE2 messenger ribonucleic acid (mRNA) is high in the nasal ciliated and goblet cells and detectable in basal, club, ciliated, and type II alveolar cells of the lower airway. Although pneumocytes and the lower respiratory tract are the key replication loci for SARS-CoV, SARS-CoV-2 replicates rapidly in upper respiratory tract tissues, thus contributing to its more effective transmission and infection dynamics than SARS-CoV.

ACE2 in post-acute sequelae of COVID-19 (PASC)

The clinical definition of PASC or long COVID by the World Health Organization (WHO) involves individuals with persistent symptoms impacting daily function for a minimum of three months after a suspected or confirmed COVID-19 infection, with symptoms remaining persistent for a minimum of two months that bears no explanation by another diagnosis.

Numerous contributory processes, including chronic immunological activation, vascular dysfunction, prolonged dysregulation of tissue ACE2, and autoantibodies, have been hypothesized for the etiology of long COVID. ACE2 dysregulation observed at the time of acute SARS-CoV-2 infection has been related to elevated mortality levels as well as acute myocardial injury.

The role of ACE2 in respiratory diseases

Low ACE2 levels are associated with the pathogenesis of acute respiratory disease syndrome (ARDS), acute lung injury (ALI), pulmonary arterial hypertension (PAH), and pulmonary fibrosis. Treating numerous organoids, cell types, or mice in vivo with recombinant RBD or spike protein from SARS-CoV and SARS-CoV-2 resulted in ACE2 downregulation from the surface of the cell as well as pulmonary function impairment and exacerbation of lung diseases. By increased RAS or bradykinin system activation, decreased ACE2 expression exacerbates the severity and pathophysiology of both acute and chronic lung damage.

In addition to inhibiting spike binding to block COVID-19 infection, the team noted that the ACE2 axis might be temporally modulated to attenuate SARS-CoV-2-induced lung diseases, providing a possible dual treatment strategy. In animal models, reconstitution of ACE2 enzymatic activity, irrespective of spike binding, also relieved lung symptoms associated with SARS-CoV-2 infections.

ACE2 and COVID-19 vaccination

COVID-19 vaccine development and SARS-CoV-2 neutralization techniques depend heavily on inhibiting the interaction of spike-RBD with ACE2. All vaccines, regardless of their underlying technologies, rely on establishing humoral immunity in response to the viral spike protein, hence inhibiting the interaction of the virus with ACE2. Profiling 127 sample antibodies from mRNA vaccination recipients indicated that at least 98% of the antibodies targeted the RBD, suggesting a prominent role in blocking ACE2 interaction for SARS-CoV-2 neutralization mediated by the vaccine.

Conclusion

The study results showed that ACE2 serves as the key entry receptor for all currently known as well as future SARS-CoV-2 variants, placing it at the center of the COVID-19 pandemic. ACE2 protects several organs and facilitates physiological homeostasis in humans, which explains the route of viral transmission and the multi-organ injury observed in acute SARS-CoV-2 infection and, subsequently, long COVID. Fundamental knowledge of the importance of ACE2 justifies ACE2-centered strategies for globally preventing and treating COVID-19.

Written by

Bhavana Kunkalikar

Bhavana Kunkalikar is a medical writer based in Goa, India. Her academic background is in Pharmaceutical sciences and she holds a Bachelor's degree in Pharmacy. Her educational background allowed her to foster an interest in anatomical and physiological sciences. Her college project work based on ‘The manifestations and causes of sickle cell anemia’ formed the stepping stone to a life-long fascination with human pathophysiology.