Human ACE2 receptor polymorphisms and altered susceptibility to SARS-CoV-2

Area of Science:

• Genetics
• Virology
• Immunology

Background:

• COVID-19, caused by SARS-CoV-2, utilizes the ACE2 receptor for host cell entry.
• The SARS-CoV-2 spike protein exhibits high affinity for the human ACE2 receptor, contributing to its infectivity.

Purpose of the Study:

• To investigate the impact of ACE2 gene polymorphisms on host susceptibility to SARS-CoV-2 infection.
• To identify specific ACE2 variants that may modulate the interaction with the SARS-CoV-2 spike protein.

Main Methods:

• Analysis of over 290,000 genomic samples from diverse populations.
• Identification of ACE2 protein-altering variants using public genomic datasets.
• In silico prediction of variant effects on spike protein binding, followed by biochemical assays and viral entry blocking experiments.

Main Results:

• Multiple ACE2 variants were identified, with some predicted to increase (e.g., S19P, K26R, T92I) and others to decrease (e.g., K31R, E37K) SARS-CoV-2 susceptibility.
• Biochemical assays confirmed altered binding affinities for variants K31R, E37K (decreased) and K26R, T92I (increased) with the spike protein.
• Soluble ACE2 variants K26R and T92I demonstrated enhanced blocking of S-protein pseudotyped virus entry.

Conclusions:

• ACE2 polymorphisms can significantly modulate host susceptibility to SARS-CoV-2.
• Specific ACE2 variants may confer either increased risk or protection against COVID-19 by altering viral binding.
• These findings highlight the role of host genetics in SARS-CoV-2 infection dynamics.