SARS-CoV2 infectivity is potentially modulated by host redox status

Area of Science:

• Biochemistry
• Virology
• Molecular Biology

Background:

• The COVID-19 pandemic, caused by SARS-CoV-2, poses a significant global threat.
• Variations in SARS-CoV-2 infection susceptibility across hosts remain unexplained.
• Viral entry involves the SARS-CoV-2 spike (S) protein binding to the host cell receptor ACE2.

Purpose of the Study:

• To investigate the role of protein structure and redox activity in SARS-CoV-2 infection.
• To explain the observed disparities in COVID-19 infection and severity among different populations and species.

Main Methods:

• Analysis of amino acid sequences for SARS-CoV-2 S-proteins and ACE2 receptors from databases.
• Examination of high-resolution protein structures to identify conserved cysteine residues and disulfide bonds.
• Comparison of ACE2 sequences between susceptible and resistant animal models.

Main Results:

• SARS-CoV-2 S-proteins and ACE2 receptors are rich in conserved cysteine residues forming intra-molecular disulfide bonds.
• Two specific disulfide bonds in the S-protein/ACE2 interaction interface are potentially redox-active.
• Resistant animal models exhibit a lack of a specific redox-active disulfide bond (Cys133-Cys141) in their ACE2 sequences.
• ACE2's role in regulating oxidative stress suggests a link between cellular oxidation and COVID-19 severity.

Conclusions:

• Redox-active disulfide bonds in the S-protein and ACE2 receptor likely facilitate SARS-CoV-2 entry.
• The redox hypothesis provides a potential explanation for COVID-19 pathogenesis and severity.
• Increased cellular oxidation in the elderly and those with comorbidities may explain their heightened vulnerability to severe COVID-19.