Bat Virus Shows Signs of Potential Spillover to Humans

A study in Nature Communications has investigated the spillover potential of merbecoviruses, a viral subgenus that includes Middle East respiratory syndrome coronavirus (MERS-CoV). Researchers from Washington State University, the California Institute of Technology and the University of North Carolina focused on how these viruses interact with host cells.

While most merbecoviruses were found unlikely to pose an immediate threat to humans, a specific subgroup, HKU5, showed genetic features that suggest it may be closer to crossing the species barrier. The researchers emphasized that HKU5’s potential to infect humans remains unrealized but deserves monitoring.

Using viral proteins to study host cell entry

Merbecoviruses, like other coronaviruses, infect cells by using spike proteins to bind to specific host receptors. The team employed virus-like particles that included only the receptor-binding portion of the spike protein to assess their ability to infect cells in vitro.

Most of the tested merbecoviruses could not effectively bind to human receptors. However, HKU5 variants used the ACE2 receptor—the same one used by SARS-CoV-2—to bind cells, though they currently do so only in bats. The researchers found that these viruses bind efficiently to the bat version of ACE2 but interact poorly with the human form.

Geographic range and host shifts

HKU5 viruses have been found across several continents, including Asia, Europe, Africa and the Middle East. The study analyzed samples collected from Japanese house bats (Pipistrellus abramus), demonstrating that certain mutations in their spike proteins can increase the binding affinity to ACE2 receptors from other species. This suggests that relatively minor genetic changes might enhance their ability to infect new hosts.

Previous studies have already shown that at least one HKU5 virus was able to infect minks in China, raising concerns about intermediate hosts enabling future zoonotic transmission.

Structural modeling with artificial intelligence

To explore viral binding at the molecular level, the researchers used AlphaFold 3, an artificial intelligence tool developed to predict protein structures. With this approach, they rapidly generated structural models of how HKU5 spike proteins might interact with ACE2 receptors. The predictions aligned closely with results obtained through traditional lab-based structural biology methods, highlighting the utility of AI tools in virology.

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Tools for monitoring and future studies

Although there is no evidence that HKU5 viruses have infected humans, the findings underscore the value of ongoing surveillance and molecular characterization of viruses circulating in wildlife. The researchers suggest that the methods developed in this study could aid in identifying other viruses with zoonotic potential and guide future investigations into vaccine or therapeutic development.

Reference: Catanzaro NJ, Wu Z, Fan C, et al. ACE2 from Pipistrellus abramus bats is a receptor for HKU5 coronaviruses. Nat Commun. 2025;16(1):4932. doi: 10.1038/s41467-025-60286-3

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