Evolutionary dynamics of heparan sulfate utilization by SARS-CoV-2

Area of Science:

• Virology
• Molecular Biology
• Cell Biology

Background:

• Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) Omicron variants exhibit increased infectivity.
• Understanding the molecular mechanisms behind Omicron's enhanced infectivity is crucial for viral surveillance and vaccine development.

Purpose of the Study:

• To identify cell surface molecules interacting with the Omicron spike protein using CRISPR library screening.
• To elucidate the role of heparan sulfate in Omicron variant infectivity and viral evolution.

Main Methods:

• CRISPR library screening to identify host cell factors.
• Comparative analysis of spike protein binding affinity to heparan sulfate.
• Mutational analysis and electrostatic potential mapping of spike protein binding sites.
• Investigation of heparan sulfate proteoglycan cleavage by TMPRSS2.

Main Results:

• Omicron spike protein shows significantly higher affinity for cell surface heparan sulfate than wild-type.
• Enhanced heparan sulfate binding allows Omicron to infect cells with low ACE2 expression.
• Positively charged mutations on the Omicron spike protein contribute to increased heparan sulfate binding.
• Heparan sulfate proteoglycans are cleaved by TMPRSS2, impacting viral infectivity.

Conclusions:

• SARS-CoV-2 Omicron variants have evolved enhanced infectivity through optimized binding to cell surface heparan sulfate.
• Heparan sulfate likely plays a critical role in the viral adaptation of SARS-CoV-2 to human hosts.
• The interaction between Omicron's heparan sulfate binding and TMPRSS2 cleavage influences viral infectivity dynamics.