In a recent study published within the Cell, researchers assessed the role of angiotensin-converting enzyme 2 (ACE2) within the coronavirus disease 2019 (COVID-19) pandemic.
Study: Angiotensin-converting enzyme 2—at the guts of the COVID-19 pandemic. Image Credit: Kateryna Kon/Shutterstock
Background
ACE2 is one of the vital commonly therapeutically targeted molecules in biomedicine on account of 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 consider regulating the ACE2 axis to functionally and structurally curb SARS-CoV-2 infections and protect against multi-organ damage. Due to this fact, knowing the precise function of ACE2 in COVID-19 is crucial for developing targeted and effective treatments.
ACE2 as an important SARS-CoV-2 entry receptor
After SARS-CoV-2 was discovered because the causal agent of COVID-19, cell culture experiments revealed that ACE2 serves as its entry receptor. Studies further discovered that each in vitro and in vivo, ACE2 is the essential receptor for each SARS-CoV and SARS-CoV-2 infections.
SARS-CoV and SARS-CoV-2 are betacoronaviruses, which most probably originated in bats. The spike protein-encoding S gene is essentially the most common locus for recombination to extend receptor binding affinities for ACE2, indicating that evolutionary adaptation of the SARS-CoV-2 receptor-binding domain (RBD) is crucial 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, regardless that certain sarbecoviruses clades have been found to have lost the power to interact with ACE2 on account of deletions and substitutions within the ACE2-binding region. On the population level in humans, ACE2 variants are prevalent but incredibly rare; nonetheless, 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 number of extrapulmonary symptoms of SARS-CoV-2 are reliant on ACE2 tissue expression and distribution. Specific to the infectious process and first viral transmission, ACE2 expression decreases from the nasal epithelium to the lower respiratory tract, correlating with viral infectivity patterns.
Expression of ACE2 messenger ribonucleic acid (mRNA) is high within the nasal ciliated and goblet cells and detectable in basal, club, ciliated, and kind II alveolar cells of the lower airway. Although pneumocytes and the lower respiratory tract are the important thing replication loci for SARS-CoV, SARS-CoV-2 replicates rapidly in upper respiratory tract tissues, thus contributing to its simpler 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 each day function for at least three months after a suspected or confirmed COVID-19 infection, with symptoms remaining persistent for at least two months that bears no explanation by one other diagnosis.
Quite a few 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 on the time of acute SARS-CoV-2 infection has been related to elevated mortality levels in addition to acute myocardial injury.
The role of ACE2 in respiratory diseases
Low ACE2 levels are related to the pathogenesis of acute respiratory disease syndrome (ARDS), acute lung injury (ALI), pulmonary arterial hypertension (PAH), and pulmonary fibrosis. Treating quite a few 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 in addition to pulmonary function impairment and exacerbation of lung diseases. By increased RAS or bradykinin system activation, decreased ACE2 expression exacerbates the severity and pathophysiology of each acute and chronic lung damage.
Along with inhibiting spike binding to dam COVID-19 infection, the team noted that the ACE2 axis may 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, no matter spike binding, also relieved lung symptoms related to 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, no matter their underlying technologies, depend 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 a minimum of 98% of the antibodies targeted the RBD, suggesting a distinguished role in blocking ACE2 interaction for SARS-CoV-2 neutralization mediated by the vaccine.
Conclusion
The study results showed that ACE2 serves as the important thing entry receptor for all currently referred to as well as future SARS-CoV-2 variants, placing it at the middle 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 stopping and treating COVID-19.