its various functions, relationship to SARS-CoV-2, and implications for COVID-19 disease sequelae

In a recent study published in the Cellresearchers 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 targeted molecules therapeutically in biomedicine due to the COVID-19 pandemic. ACE2 alters the balance of the peptide cascade as an enzyme, and as a chaperone it regulates the intestinal absorption of amino acids. Current studies focus 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 entry receptor of SARS-CoV-2

After SARS-CoV-2 was discovered as the causative agent of COVID-19, cell culture experiments revealed that ACE2 served as an entry receptor. Studies have further found that both in vitro And liveACE2 is the essential receptor for SARS-CoV and SARS-CoV-2 infections.

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

Indicative of fundamental physiological functions of ACE2, ACE2 orthologs are widely conserved across all vertebrate species and have even been detected in insects. The evolutionary interplay between ACE2 amino acid residues that interact with SARS-CoV and SARS-CoV-2 RBDs explains the broad host tropism, promoting zoonotic transmission and viral development of SARS-CoV- 2.

All related to SARS coronavirus bind to ACE2 with varying affinities, although some sarbecovirus 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 widespread but incredibly rare; however, structural and functional analyzes reveal that some human ACE2 variants can promote or inhibit spike protein binding.

SARS-CoV-2 infections facilitated by ACE2 delivery

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

Expression of messenger ribonucleic acid ACE2 (mRNA) is elevated in nasal ciliate and goblet cells and detectable in basal, club, ciliate, and alveolar type II cells of the lower respiratory tract. Although pneumocytes and the lower respiratory tract are major replication loci for SARS-CoV, SARS-CoV-2 replicates rapidly in upper respiratory tract tissues, contributing to its more efficient 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 people with persistent symptoms affecting daily function for at least three months after a suspected or confirmed COVID-19 infection, with symptoms remaining persistent for at least two months. which does not support any explanation by another diagnosis.

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

The role of ACE2 in respiratory diseases

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

In addition to inhibiting spike binding to block COVID-19 infection, the team noted that the ACE2 axis could be modulated over time to attenuate SARS-CoV-2-induced lung disease, providing a possible dual treatment strategy. In animal models, reconstitution of ACE2 enzyme activity, independent of spike binding, also relieved pulmonary symptoms associated with SARS-CoV-2 infections.

ACE2 and COVID-19 vaccination

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

Conclusion

Study results showed that ACE2 serves as a key entry receptor for all currently known and future SARS-CoV-2 variants, placing it at the center of the COVID-19 pandemic. ACE2 protects multiple organs and facilitates physiological homeostasis in humans, explaining the viral transmission route and multi-organ damage seen in acute SARS-CoV-2 infection and subsequently. the long COVID. Fundamental knowledge of the importance of ACE2 justifies ACE2-centric strategies to prevent and treat COVID-19 globally.