Distinct pathways for evolution of enhanced receptor binding and cell entry in SARS-like bat coronaviruses

Area of Science:

• Virology
• Molecular Biology
• Infectious Diseases

Background:

• Bat coronaviruses (CoVs) are a significant zoonotic threat, necessitating research into their transmission potential.
• Understanding viral adaptation mechanisms is crucial for predicting and preventing future pandemics.

Purpose of the Study:

• To investigate the cell entry mechanisms of bat CoVs.
• To identify genetic adaptations that enhance viral entry and host-specific interactions.

Main Methods:

• Generation of recombinant vesicular stomatitis viruses (rVSVs) expressing bat CoV spike proteins.
• Analysis of viral entry efficiency and spike protein interactions with the ACE2 receptor.
• Identification of key amino acid substitutions through viral rescue and serial passage.

Main Results:

• A novel substitution in the S2 fusion peptide-proximal region (FPPR) of SHC014-CoV spike enhanced viral entry.
• This FPPR substitution increased spike receptor-binding domain availability for ACE2 recognition.
• A second substitution in the S1 N-terminal domain further boosted spike:ACE2 interaction and viral entry.

Conclusions:

• Identified specific genetic pathways enabling bat CoV adaptation for spillover and transmission.
• Highlighted fitness trade-offs associated with these adaptive mutations.
• Revealed potential vulnerabilities in bat CoV entry mechanisms for targeted countermeasures.