The emergence of new variants of the SARS-CoV-2 virus during the COVID-19 pandemic has intrigued scientists, who are eager to understand the factors driving their evolution. While the role of the immune system in shaping viral evolution has been extensively studied, recent research suggests that the cellular receptor ACE2 may also play a significant role. French scientists from CNRS, Aix Marseille Université, and INSERM have put forward a hypothesis that rare alleles of human ACE2 contribute to the emergence of immune evasive SARS-CoV-2 variants.
Traditionally, it has been believed that the immune response in humans, including the production of neutralizing antibodies, is a major factor in shaping the genetic diversity of SARS-CoV-2. When an individual becomes infected with the virus, their immune system mounts a defense, which triggers the virus to evolve in response. This immune pressure can lead to the emergence of immune-evasive variants. For example, the use of monoclonal antibody therapies has resulted in the selection of SARS-CoV-2 mutants that are less susceptible to these antibodies. Immunocompromised patients with chronic infections also exhibit a higher genetic diversity of the virus. The role of the immune system in shaping SARS-CoV-2’s genetic diversity is well-established.
However, recent research has shed light on the potential role of the virus’s cellular receptor, ACE2. ACE2 is the receptor to which the virus binds during infection. The interaction between the virus’s spike protein and the host’s ACE2 receptor may exert selective pressure on the virus’s genetic evolution. ACE2 is not only crucial for viral attachment but also plays a role in the pathophysiology of COVID-19, adding complexity to the virus-host interaction.
Various factors contribute to the genetic drift of SARS-CoV-2, including viral mutations and host factors. ACE2 polymorphism, in particular, seems to play a significant role. Previously, it was believed that mutations in the viral spike protein occurred in response to the selective pressure of neutralizing antibodies. However, recent studies have challenged this perspective. Host-specific mutations, such as the Y453F mutation, have been observed in animal hosts like mink, deer, and hamsters, indicating the role of host-specific ACE2 polymorphisms.
One intriguing aspect of SARS-CoV-2 variants is the emergence of those with the N501Y substitution. It is hypothesized that rare ACE2 alleles may play a pivotal role in the selection of these variants. 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 interaction between the N501Y variant and the E329G substitution in ACE2 is more favorable.
The hypothesis that rare ACE2 alleles contribute to the emergence of immune evasive SARS-CoV-2 variants opens up new avenues for research. While it may be challenging to trace the exact origin of these variants, laboratory experiments could provide valuable insights into the emergence of N501Y variants. Understanding the interplay between the immune system, cellular receptors, and viral genetic drift may have implications for the development of strategies to combat viral infections. This model of virus selection driven by adaptation to the receptor could also be applicable to other viruses and their respective receptors, expanding our understanding of virus evolution. The intricate relationship 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.