Cell-based receptor discovery identifies host factors specifically targeted by the SARS CoV-2 spike

Area of Science:

• Cellular biology
• Virology
• Immunology

Background:

• Receptor-ligand interactions are crucial for cellular communication and viral infections.
• Characterizing these interactions is vital for drug development but technologically challenging.
• Existing technologies lack the capacity for high-throughput, systematic interactome analysis.

Purpose of the Study:

• To develop a novel high-throughput cell-based platform for characterizing receptor-ligand interactomes.
• To identify host factors targeted by the SARS-CoV-2 spike protein's receptor binding domain (RBD).
• To uncover specific SARS-CoV-2 host factors for improved therapeutic strategies.

Main Methods:

• Engineered a library of human proteins for controlled cell surface expression.
• Utilized tetramer-based screening to enhance binding avidity.
• Developed a high-throughput cell-based platform for systematic interactome interrogation.
• Characterized cell surface proteins targeted by SARS-CoV spike protein RBD.

Main Results:

• Identified host factors specifically binding to SARS-CoV-2 but not SARS-CoV RBD.
• Discovered proteins expressed in the nervous system and olfactory epithelium as potential targets.
• Found Contactin-1, a novel SARS-CoV-2 spike-specific receptor, upregulated in COVID-19 patients.
• Demonstrated Contactin-1 significantly enhances ACE2-dependent pseudotyped virus infection.

Conclusions:

• The developed platform enables systematic characterization of cell surface interactomes.
• Identified Contactin-1 as a key host factor enhancing SARS-CoV-2 infection.
• Findings provide crucial information for designing targeted therapeutic strategies against COVID-19.