Multiple independent acquisitions of ACE2 usage in MERS-related coronaviruses.

Summary

Two European bat MERS-related coronaviruses use ACE2 via a binding interface located >45 Å from any previously known ACE2 footprint. Broad ACE2 ortholog screening identified key host tropism determinants, including ACE2 N432 glycosylation, and enabled the design of a potent soluble bat ACE2 decoy that neutralizes these viruses.

Key Findings

• Cryo-EM reveals an ACE2-binding mode >45 Å away from all known ACE2-using coronavirus interfaces.
• ACE2 ortholog profiling across 105 mammals identified host tropism determinants, including ACE2 N432 glycosylation that restricts recognition.
• A soluble Pipistrellus nathusii ACE2 mutant was engineered with potent neutralizing activity against these bat merbecoviruses.

Clinical Implications

Improves surveillance prioritization by highlighting ACE2 glycosylation and single-site constraints governing host range; supports development of decoy receptors and cross-protective therapeutics against emergent merbecoviruses.

Limitations

• Findings are based on in vitro and structural analyses without demonstration of human infection dynamics.
• Narrow ACE2 ortholog specificity suggests limited host range for the studied strains, requiring broader sampling.

Future Directions

Test decoy ACE2 constructs and inhibitors in vivo, expand surveillance to additional merbecovirus clades, and assess spillover potential using human airway organoids and animal challenge models.