MUST READ! French Scientists Present The ‘Boomerang Effect Hypothesis’ Of SARS-CoV-2 Evolution And ACE2 Receptor Polymorphism And Possible Threats

The "boomerang effect" raises concerns about the emergence of variants less susceptible to neutralizing antibodies, potentially hindering vaccine effectiveness and possibly being more pathogenic and even lethal.
 
COVID-19 News: The COVID-19 pandemic caused by the SARS-CoV-2 virus has presented numerous challenges worldwide. As the virus continues to evolve, understanding its genetic variations and their implications becomes increasingly important. Recent research by French researchers from Aix-Marseille Université, Centre National de la Recherche Scientifique and INSERM UMR-France has shed light on the ACE2 receptor polymorphism in both humans and animals, revealing its role in the emergence of SARS-CoV-2 variants during host-switching events. This phenomenon, known as the "boomerang effect," poses potential risks and complicates efforts to effectively combat the virus.


Illustration of the ACE2-driven “Boomerang effect” that positively selects SARS-CoV-2 variants for their binding affinity to the host ACE2 during intra- (human to human) and inter-species (human-to-mink and mink-to-human) transmission of the virus. Box (upper right): schematic representation of the SARS-CoV-2 spike (S) protein from B1.1 (1,273 amino acids), B1.1.7 and B1.1.298 lineages. The Spike (S) protein is comprised of an N-terminal subunit (S1) that mediates the receptor binding and a C-terminal subunit (S2) responsible for virus-cell membrane fusion. NTD: N-terminal domain; RBD, receptor-binding domain; FP, fusion peptide; TM, single-span transmembrane domain.

The Evolutionary Dynamics of SARS-CoV-2 Variants
SARS-CoV-2, like other coronaviruses, has the ability to spread between humans and animals. Genetic analysis has shown a high frequency of mutations in both human and animal isolates, suggesting positive selection in various ecological niches. While the host-specific immune response is a primary driver of viral mutations, the initial interaction between the viral spike protein and the ACE2 receptor plays a crucial role. ACE2 exhibits significant polymorphism within and across species, potentially influencing the virus's ability to bind and enter host cells.
 
Impact of ACE2 Polymorphism on Viral Fitness
When the interaction between the viral spike protein and ACE2 receptor is suboptimal due to host-switching, mutations can be selected to improve affinity for the ACE2 receptor of the new host. The spike receptor binding domain (RBD) of SARS-CoV-2, in particular, is prone to mutations that enhance its affinity for ACE2 orthologs in animals. Similarly, rare human alleles of ACE2 may also impact viral adaptation when the virus spreads among large populations. For instance, the rare E329G allele of ACE2, more prevalent in European populations, has been associated with improved affinity for the SARS-CoV-2 N501Y variant. This suggests that the emergence of the N501Y variant may have occurred in a human carrying the E329G allele of ACE2, potentially affecting viral replication and the effectiveness of neutralizing antibodies.
 
Succession of SARS-CoV-2 Variants: Implications and Challenges
Since the emergence of SARS-CoV-2, var ious variants have been observed, including D614G, B.1.1.7 (Alpha), B.1.351 (Beta), B.1.617 (Delta), and the most recent Omicron variant (B.1.1.529). These variants exhibit mutations in the spike protein, particularly in the receptor-binding domain (RBD) and the N-terminal domain (NTD). The presence of mutations in both domains enhances the virus's ability to adhere to host cells as covered in previous studies and COVID-19 News reports. Some mutations affect the spike protein's affinity for ACE2, while others alter its interaction with lipid rafts, influencing virus adhesion kinetics.
 
The ACE2-Driven "Boomerang Effect" Model
The emergence and circulation of SARS-CoV-2 variants can be explained by the ACE2-driven "boomerang effect" model. According to this model, the virus replicates in individuals with a specific ACE2 receptor (A), infects individuals with a different ACE2 receptor (B), mutates to adapt to the ACE2 receptor of individual B, and subsequently returns to the A population with altered properties. This model highlights the potential for genetic drift and the emergence of novel strains through repeated intra- and inter-species transmission of SARS-CoV-2.
 
The Role of ACE2 in Inter-Species Transmission
The traditional concept of a "species barrier" as the primary determinant of viral transmission is being challenged. SARS-CoV-2 has demonstrated the ability to infect a wide range of species, indicating that viral transmission is primarily determined by the interaction between the virus and the host receptor, such as ACE2. ACE2 polymorphism plays a crucial role in determining host susceptibility and viral adaptation. Reports of SARS-CoV-2 infections in animals further emphasize the importance of understanding ACE2 receptor variation and its impact on viral circulation.
 
Implications of the ACE2-Driven "Boomerang Effect"
The risks associated with the ACE2-driven "boomerang effect" are significant. The reintroduction of variant viruses adapted to a specific ACE2 receptor poses challenges in terms of viral control and prevention. Previous outbreaks, such as the SARS-CoV-1 epidemic, have demonstrated that mutations in the spike protein can enhance transmission from animals to humans. The "boomerang effect" raises concerns about the emergence of variants less susceptible to neutralizing antibodies, potentially hindering vaccine effectiveness.
 
Conclusion
The ACE2 receptor polymorphism plays a critical role in the emergence of SARS-CoV-2 variants during intra- and inter-species host-switching. The "boomerang effect" highlights the potential risks and challenges in controlling the virus as it continues to evolve. Understanding the dynamics of ACE2-driven viral adaptation is crucial for developing effective strategies to combat the ongoing COVID-19 pandemic and prevent the emergence of new variant strains.
 
Further Discussions
In this study, evidence is presented to support the notion that adaptation to the ACE2 polymorphism is a major determinant of the multiple waves of the SARS-CoV-2 pandemic through lineage replacement. Inter-species transmission of the virus can lead to the selection of mutations specifically aimed at improving viral fitness to ACE2 orthologs. The emergence of the Omicron variant, for example, shows a high number of mutations in the spike protein, particularly in the N-terminal domain (NTD). This suggests a genetic drift to better fit the ACE2 of its main animal host, possibly the mouse ACE2. This observation raises concerns about the efficacy of current vaccines against these newer subvariants that possess enhanced transmissibility and the ability to evade neutralizing antibodies.
 
Although not all SARS-CoV-2 lineages are the result of inter-species transmission, it is possible that certain variants have been determined by the ACE2 polymorphism in humans. The N501Y substitution in the SARS-CoV-2 spike protein, for example, emerged in humans without any known inter-species transmission. The rare ACE2 allele E329G, prevalent in European populations, has been shown to have a favorable interaction with the mutated spike protein N501Y.
 
This suggests that the selection of the N501Y UK variant B1.1.7 may have occurred in individuals carrying the E329G allele of ACE2. These findings support the idea of ACE2-driven variant selection during intra-species transmission, contributing to the evolution of SARS-CoV-2 lineages over time.
 
Overall, understanding the interplay between ACE2 receptor polymorphism and viral adaptation is crucial for addressing the challenges posed by SARS-CoV-2 variants. This knowledge can guide the development of effective strategies to control the ongoing pandemic and mitigate the emergence of new variant strains. Additionally, these insights may have broader implications for understanding viral dynamics and adaptation to other viruses and their cellular receptors.\
 
The study findings were published in the peer reviewed journal: Frontiers in Microbiology.
https://www.frontiersin.org/articles/10.3389/fmicb.2023.1199561/full
 
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