A group of bat viruses closely related to the Middle East Respiratory Syndrome coronavirus (MERS-CoV) could be just one small mutation away from spilling over into human populations, potentially causing the next pandemic. This concerning discovery comes from a recent study published in the journal Nature Communications, involving scientists from Washington State University (WSU), the California Institute of Technology, and the University of North Carolina. Michael Letko, a virologist at WSU's College of Veterinary Medicine and a key figure in the study, explains that merbecoviruses, the subgenus that includes MERS-CoV, have been largely underexplored. His team aimed to fill this knowledge gap by investigating how these viruses infect cells. While most merbecoviruses present minimal threats to humans, the subgroup known as HKU5 has raised significant concerns. Similar to SARS-CoV-2, which caused the COVID-19 pandemic, HKU5 viruses rely on the spike protein to bind to the ACE2 receptor, crucial for invading host cells. However, unlike SARS-CoV-2, HKU5 viruses currently interact primarily with the ACE2 receptor in bats and not as effectively with the human version. Letko's team identified specific mutations in the HKU5 spike protein that could enable the viruses to bind more readily to human ACE2 receptors, raising the possibility of cross-species transmission. The study focused on HKU5 viruses found in Japan, where the natural host is the Japanese house bat (Pipistrellus abramus). Researchers conducted lab tests using virus-like particles with the spike protein to assess their ability to infect different cell types. They found that certain mutations could significantly enhance the viruses' ability to bind to and infect human cells. Further supporting this concern, a separate study earlier this year revealed that an HKU5 virus in China had already jumped to minks, indicating its potential to cross species barriers. Although there is no evidence yet of these viruses infecting humans, their close relation to MERS-CoV and their documented spillover capability make them a serious subject for ongoing surveillance and research. Victoria Jefferson, a postdoctoral researcher at WSU, utilized AlphaFold 3, an advanced artificial intelligence program, to model the binding of the HKU5 spike protein to the ACE2 receptor at the molecular level. This technique, which traditionally requires months of lab work and specialized equipment, yielded accurate predictions within minutes. The findings align with those from traditional approaches, validating the efficacy of AI in accelerating structural analysis and potentially aiding in the development of new vaccines and treatments. Letko emphasized that the methods and findings of this study could serve as a foundation for future research, helping to identify and mitigate emerging viral threats. Given the high mortality rate of MERS-CoV (approximately 34%), the discovery of HKU5’s potential to spill over into humans underscores the importance of proactive monitoring and preparedness in the field of virology. Industry insiders laud the study for its innovative use of AI to advance virological research. The rapid and accurate modeling capabilities of AlphaFold 3 could revolutionize how scientists approach the study of zoonotic diseases, enabling quicker identification of virus threats and facilitating the development of targeted interventions. WSU, known for its robust veterinary medicine and global health programs, continues to play a pivotal role in this critical area of research, contributing valuable insights and tools to the scientific community.