Human ACE2 Genetic Polymorphism Affecting SARS-CoV and SARS-CoV-2 Entry into Cells.

Area of Science:

• Virology
• Genetics
• Molecular Biology

Background:

• Severe acute respiratory syndrome coronavirus (SARS-CoV) and SARS-CoV-2 utilize the human angiotensin-converting enzyme 2 (ACE2) receptor for cell entry.
• Previous research indicated that single nucleotide variants (SNVs) in ACE2 might affect binding affinity to the SARS-CoV-2 spike (S) protein's receptor-binding domain (RBD).

Purpose of the Study:

• To investigate the functional impact of reported ACE2 SNV substitutions on SARS-CoV and SARS-CoV-2 entry into host cells.
• To determine if ACE2 genetic variations influence cellular susceptibility to these coronaviruses.

Main Methods:

• Utilized vesicular stomatitis Indiana virus (VSIV) pseudotyped with SARS-CoV and SARS-CoV-2 S proteins to model viral entry.
• Transfected HEK293T cells with plasmids encoding ACE2 variants with specific SNV substitutions.
• Assessed relative infectivity by measuring pseudotyped VSIV entry into cells expressing ACE2 variants compared to wild-type ACE2.

Main Results:

• Several ACE2 SNV substitutions demonstrated a significant positive or negative effect on pseudotyped virus infectivity.
• The H505R substitution in ACE2 notably enhanced infection, particularly with pseudotyped viruses carrying S protein RBDs from SARS-CoV-2 variants of concern.
• Findings suggest ACE2 genetic polymorphisms can modulate cellular susceptibility to SARS-CoV and SARS-CoV-2.

Conclusions:

• Human ACE2 SNVs can functionally impact the efficiency of SARS-CoV and SARS-CoV-2 cell entry.
• Genetic variations in ACE2 may play a role in determining individual or population susceptibility to coronavirus infections.
• This study highlights the importance of considering host genetic factors in understanding coronavirus pathogenesis and spread.