COVID-19 News: French Scientists Hypothesize That Rare Alleles Of Human ACE2 Are Contributing To The Emergence Of Immune Evasive SARS-CoV-2 Variants
The COVID-19 pandemic has brought about a significant wave of genetic evolution within the SARS-CoV-2 virus. The continuous replacement of viral lineages with new variants has puzzled scientists and raised questions about the driving forces behind these mutations. Traditionally, the immune system's role in shaping viral evolution has been a central focus. However, emerging research from French scientists at the Centre National de la Recherche Scientifique (CNRS), Aix Marseille Université, and Institut National de la Santé et de la Recherche Médicale (INSERM) suggests that the cellular receptor, ACE2, may also play a pivotal role in the selection of SARS-CoV-2 variants. This COVID-19 News
report delves into the intriguing hypothesis that rare alleles of human ACE2 are contributing to the emergence of immune evasive SARS-CoV-2 variants.
Hypothetical model of immune escape by selection pressure at the level of the viral receptor. This model proposes the intervention of an individual expressing a rare allele of ACE2 (E329G) in the selection of the N501Y lineage of SARS-CoV-2 then its transmission to human populations expressing the major ACE2 (E329) allele. In this model, three main forces act on the genetic drift of the virus: the fitness capacity of the virus, the sequence of the host’s ACE2 serving as a receptor for the virus and, the host’s anti-SARS-CoV-2 immune response.
Role of the Immune System in Selecting SARS-CoV-2 Variants
The immune response in humans, including the production of neutralizing antibodies, plays a crucial role in shaping the genetic diversity of SARS-CoV-2. When an individual encounters the virus, their immune system is triggered to mount a defense. This immune response, which may include the production of antibodies, aims to neutralize the virus. The virus, however, doesn't sit idly by; it evolves in response to this immune pressure.
Intra-host analysis of SARS-CoV-2 evolution has shown that multiple viral mutants exist within a single infected individual. While one "master mutant" often dominates, minor mutants can gain an advantage under selective pressure. This phenomenon, driven by the host's immune response, can ultimately lead to the emergence of immune-evasive variants.
For instance, monoclonal antibodies targeting the spike protein of the virus have been used as therapies. However, this therapeutic use has led to the selection of SARS-CoV-2 spike protein mutants that are less susceptible to these antibodies. Cases of variants with critical spike mutations, such as E484K and N501Y, have been reported after monoclonal antibody therapy. Moreover, immunocompromised patients with chronic SARS-CoV-2 infections have shown a higher genetic diversity of the virus, with a tendency for these variants to harbor spike protein mutations. The immune system's role in shaping SARS-CoV-2's genetic diversity is undeniably significant.
The Cellular Receptor ACE2: A Key Player in SARS-CoV-2 Evolution
While the immune system's i
nfluence on SARS-CoV-2 evolution has been well-studied, the role of the virus's cellular receptor, ACE2, has gained increasing attention. ACE2 is the receptor to which the SARS-CoV-2 virus binds during infection. Recent findings have indicated that the interaction between the virus's spike protein and the host's ACE2 receptor may also exert selective pressure on the virus's genetic evolution.
It's important to note that, in the initial months following the emergence of SARS-CoV-2, ACE2 was identified as the receptor for the virus. Beyond its role in viral attachment, ACE2 is crucial in the pathophysiology of COVID-19, adding another layer of complexity to the virus-host interaction.
Role of ACE2 in the Genetic Drift of SARS-CoV-2
The genetic drift of SARS-CoV-2 is driven by several factors, including viral mutations and host factors. Among these, ACE2 polymorphism plays a noteworthy role. The virus's polymerase is known to introduce errors during replication, leading to the emergence of new viral lineages. Additionally, host factors like the apolipoprotein B mRNA editing enzymes (APOBEC) and adenosine deaminase acting on RNA (ADAR) systems, as well as the immune system's selective pressure, contribute to viral genome evolution.
Previously, it was widely accepted that most mutations in the viral spike protein occurred in response to the selective pressure of neutralizing antibodies. Some of these mutations even increased the spike protein's affinity for ACE2. However, recent studies have challenged this perspective.
Research on SARS-CoV-2 sequences in mink, for example, revealed that host-specific mutations, like the Y453F mutation, could give the virus an advantage in replication within mink. This mutation, though advantageous in mink, was neutral when the virus transmitted to humans. The adaptation of SARS-CoV-2 in other animal hosts, like deer and hamsters, has shown similar host-specific mutations in the spike protein, emphasizing the role of host-specific ACE2 polymorphisms.
The Role of Rare ACE2 Alleles
The emergence of SARS-CoV-2 variants with the N501Y substitution, a mutation of concern, has intrigued scientists. It has been hypothesized that rare ACE2 alleles could play a pivotal role in the selection of these variants. The human genome project has revealed that ACE2 is a polymorphic molecule, with certain alleles being more prevalent in specific regions.
Recent evidence suggests that an N501Y variant could be selected when SARS-CoV-2 with an N501 spike protein is transmitted to individuals with a rare ACE2 allele expressing E329G. This rare allele is found in the European population but absent in Asian populations. The N501Y variant of concern, which first emerged in the UK, is more favorable for interaction with the E329G substitution in ACE2.
Discussion and Implications
The dynamic evolution of the N501Y lineage of SARS-CoV-2 has raised intriguing questions. While it's not possible to definitively prove that rare ACE2 alleles were solely responsible for the emergence of N501Y variants, the hypothesis is tantalizing. The role of ACE2 alleles in human-to-human transmission and inter-species transmission, particularly to mink, has provided insights into the selection of SARS-CoV-2 variants.
The ACE2 gene's location on the X chromosome further supports the idea that rare ACE2 alleles may have played a role in the emergence of N501Y variants. Although it may be challenging to trace the exact origin of these variants after more than three years, in vitro experiments could provide a new perspective. By studying the serial passages of an ancestral SARS-CoV-2 in cells expressing ACE2 with the E329G substitution, researchers may be able to observe the emergence of N501Y variants.
Furthermore, this model of virus selection driven by adaptation to the receptor is not limited to the ACE2 receptor alone. It opens the door to exploring similar mechanisms in other viruses and their respective receptors, providing a new dimension to the study of virus evolution. Understanding the dual role of the immune system and cellular receptors in viral genetic drift may shed light on future approaches to combating viral infections.
The emergence of SARS-CoV-2 variants has been a central concern during the COVID-19 pandemic. While the immune system's role in shaping viral evolution has been extensively studied, the impact of the virus's cellular receptor, ACE2, has gained prominence. The hypothesis that rare ACE2 alleles contribute to the emergence of immune evasive variants, such as N501Y, offers an exciting avenue for future research. By considering the dual role of the immune system and cellular receptors in viral genetic drift, we may uncover new insights into the dynamics of viral evolution and potentially apply this knowledge to combat other viral infections. The intricate interplay between the virus and its host, as well as the genetic diversity within human populations, continues to be a captivating subject of study in the field of virology.
The hypothesis was published as a perspective article in the peer reviewed journal: Frontiers in Immunology.
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