Bat-infecting merbecovirus HKU5-CoV lineage 2 can use human ACE2 as a cell entry receptor.

Summary

A bat HKU5-CoV lineage 2 virus was identified that efficiently uses human ACE2, with a receptor-binding footprint overlapping sarbecoviruses. Authentic virus infected hACE2 cell lines and human respiratory/enteric organoids, indicating broad tropism and enhanced adaptation versus lineage 1. These findings elevate the zoonotic risk profile of merbecoviruses.

Key Findings

• HKU5-CoV lineage 2 efficiently utilizes human ACE2 as an entry receptor.
• Cryo-EM reveals a distinct RBD–ACE2 binding mode with a footprint overlapping ACE2-using sarbecoviruses and NL63.
• Authentic HKU5-CoV-2 infects hACE2-expressing cell lines and human respiratory and enteric organoids.
• Lineage 2 shows better adaptation to human ACE2 than lineage 1 HKU5-CoV.

Clinical Implications

Enhances surveillance priorities for merbecoviruses, supports functional receptor screening of animal coronaviruses, and guides countermeasure development (vaccines/antivirals) targeting ACE2-using emergent strains.

Limitations

• In vivo pathogenicity and transmissibility were not assessed
• Prevalence and ecological dynamics of HKU5-CoV-2 in bats remain undefined

Future Directions

Assess in vivo pathogenicity/transmission, map receptor usage across merbecoviruses, and evaluate cross-neutralization and antiviral susceptibility to inform countermeasures.