MERS Cousins Switch to ACE2, Raising New Pandemic Concerns

According to Nature, researchers have discovered that HKU25 clade coronaviruses – previously classified as MERS-related viruses – actually use ACE2 receptors rather than DPP4 for cellular entry. The study analyzed 152 non-redundant merbecovirus spike sequences and found that most HKU25 clade viruses can engage ACE2, with EjCoV-3 showing broad ACE2 tropism including suboptimal human ACE2 utilization. Cryo-electron microscopy at 2.5 Å resolution confirmed ACE2 binding with structural similarities to HKU5 coronavirus, while functional assays revealed these viruses require trypsin-dependent activation and show sensitivity to TMPRSS2 inhibitors. This receptor switch fundamentally changes our understanding of these viruses’ spillover potential.

The Receptor Reclassification That Changes Everything

This discovery represents one of the most significant coronavirus receptor reclassifications since the emergence of SARS-CoV-2. The HKU25 clade viruses were previously categorized as MERS-related coronaviruses based on sequence homology and phylogenetic relationships, which suggested they should use DPP4 receptors like their MERS-CoV cousins. The finding that they’ve evolutionarily switched to ACE2 usage is comparable to discovering a distant relative has developed entirely different biological capabilities than their immediate family. This isn’t just an academic distinction – it fundamentally alters how we assess their pandemic potential, since ACE2-using coronaviruses have already demonstrated their ability to cause global outbreaks.

What Cryo-EM Reveals About Evolutionary Pathways

The cryogenic electron microscopy data showing 2.5 Ångström resolution structures provides unprecedented insight into coronavirus evolution. The fact that HKU25 clade RBDs engage ACE2 with binding poses similar to HKU5, burying 870-1,016 Ų of surface area, suggests convergent evolution toward ACE2 utilization across different coronavirus lineages. This isn’t random mutation – it’s directed evolutionary pressure favoring ACE2 as an entry point. The conservation of 15 out of 24 ACE2-interacting residues from HKU5 in HKU25 clade RBDs indicates this receptor preference is deeply embedded in their protein primary structure, not a recent adaptation.

The Practical Implications for Pandemic Preparedness

From a public health perspective, the most concerning finding is EjCoV-3’s ability to utilize human ACE2, even if suboptimally. In virology, “suboptimal” doesn’t mean “safe” – it means the virus has already overcome the biggest barrier to human infection and now just needs refinement. The broad ACE2 tropism across mammalian orders suggests these viruses could use multiple animal species as intermediate hosts, creating numerous pathways for human spillover. The trypsin dependence and TMPRSS2 sensitivity mean these viruses might respond to some of the same therapeutic approaches developed for SARS-CoV-2, but their distinct structural features mean they could evade existing antibodies and vaccines.

The Surveillance Gaps This Discovery Exposes

This research reveals critical weaknesses in our current coronavirus surveillance approach. The fact that these viruses were misclassified for years based on incomplete receptor data suggests we’re making dangerous assumptions about emerging pathogens. The wide geographical distribution of HKU25 clade viruses across Eurasia in multiple bat species means this isn’t an isolated phenomenon – it’s a widespread evolutionary trend we’ve been missing. Our surveillance systems typically look for viruses similar to known threats, but this discovery shows we need to cast a much wider net and functionally test receptor usage rather than relying solely on genetic sequencing.

The Protective Role of Glycan Barriers

One of the most hopeful findings is that glycans near the ACE2 interaction interface appear to act as natural host-tropism barriers for HKU25 clade coronaviruses. The study showed that removing these glycans generally enhanced binding, while glycan knock-in mutations often abolished it. This suggests human ACE2 has built-in structural defenses against these viruses that don’t exist against SARS-CoV-2. However, the finding that specific mutations can overcome these barriers means we can’t rely on natural protection indefinitely – evolutionary pressure could eventually select for variants that bypass these glycan obstacles.

The Changing Therapeutic Landscape

The sensitivity to TMPRSS2 inhibitors like Camostat suggests some existing coronavirus therapeutics might have broad applicability, but the varied half-maximal inhibitory concentrations across strains means we can’t assume one-size-fits-all solutions. The absence of a polybasic cleavage site distinguishes these viruses from both SARS-CoV-2 and MERS-CoV, meaning they might require different activation pathways and could be susceptible to different classes of protease inhibitors. This discovery essentially creates a new category of coronaviruses that straddle the therapeutic profiles of both major pandemic coronaviruses, requiring tailored approaches for prevention and treatment.