HKU5 bat merbecoviruses engage bat and mink ACE2 as entry receptors

Understanding how bat coronaviruses enter cells is key to predicting which ones might infect other animals or humans in the future. In this study, we investigated a bat coronavirus called HKU5, a close relative of the virus that causes Middle East Respiratory Syndrome (MERS). While the MERS virus uses a protein called DPP4 to enter cells, we discovered that HKU5 instead uses another protein, ACE2, found on the surface of animal cells. We showed that HKU5 can attach to and enter cells using ACE2 from bats, but not the human version of ACE2. Structural studies revealed that HKU5 binds to ACE2 in a different way from other ACE2-using coronaviruses, such as SARS-CoV or SARS-CoV-2. Interestingly, HKU5 can also use ACE2 from mink and stoats, suggesting these animals might serve as bridge hosts between bats and other species. This work improves our understanding of how coronaviruses adapt to new hosts and informs strategies for monitoring and preventing future outbreaks.