Discovery of HKU5-CoV-2: A New Bat Coronavirus with Zoonotic Potential

A Chinese research team led by virologist Shi Zhengli at the Wuhan Institute of Virology has identified a novel bat coronavirus, HKU5-CoV-2, which utilizes the human angiotensin-converting enzyme 2 (ACE2) receptor to infect cells—a mechanism shared with SARS-CoV-2, the virus responsible for the COVID-19 pandemic. Published in Cell on February 21, 2025, the study reveals that HKU5-CoV-2 belongs to the merbecovirus family, which includes Middle East respiratory syndrome coronavirus (MERS-CoV). While lab experiments demonstrate the virus’s ability to infect human respiratory and intestinal organoids, its binding affinity to ACE2 is significantly weaker than that of SARS-CoV-2, suggesting limited immediate pandemic risk. Experts caution that the discovery underscores the need for ongoing surveillance of bat-borne coronaviruses, particularly given the genetic diversity and zoonotic potential of merbecoviruses.

Virological Characteristics of HKU5-CoV-2

ACE2 Receptor Utilization and Host Tropism

HKU5-CoV-2, a lineage 2 variant of the Pipistrellus bat coronavirus HKU5, employs the ACE2 receptor to gain entry into human cells, a trait it shares with SARS-CoV-2 and the common cold coronavirus NL631 3 5. Cryo-electron microscopy (cryo-EM) analysis of the virus’s receptor-binding domain (RBD) reveals a unique interaction with ACE2 that diverges from other merbecoviruses, instead resembling the binding patterns of sarbecoviruses like SARS-CoV-24 6. This structural adaptation enables HKU5-CoV-2 to infect a broad range of hosts, including humans, bats, and other mammals, raising concerns about cross-species transmission3 5.

Despite its ACE2-binding capability, kinetic studies show that HKU5-CoV-2 exhibits approximately 10-fold lower binding affinity compared to SARS-CoV-2, likely limiting its efficiency in human-to-human spread1 4. This reduced affinity stems from differences in key contact residues within the RBD-ACE2 interface, as detailed in the Cell publication6. Nevertheless, the virus’s ability to exploit a receptor ubiquitously expressed in human tissues—including the lungs, intestines, and kidneys—highlights its potential to cause systemic infections3 5.

Infection in Human Organoid Models

Experimental infections using human respiratory and intestinal organoids confirmed HKU5-CoV-2’s capacity to replicate in vitro3 6. The virus demonstrated robust replication in lung organoids, mimicking the tropism of SARS-CoV-2, and also infected intestinal tissues, suggesting a possible fecal-oral transmission route5 6. These findings align with previous observations of SARS-CoV-2’s gastrointestinal involvement but contrast with MERS-CoV, which primarily targets the lower respiratory tract2 5.

Structural and Functional Insights from Cryo-EM

Unique Binding Mode and Evolutionary Implications

Cryo-EM structural analysis of the HKU5-CoV-2 RBD-ACE2 complex uncovered a binding footprint largely overlapping with SARS-CoV-2 and NL63, despite belonging to a different coronavirus genus (merbecovirus vs. sarbecovirus)4 6. This convergent evolution suggests that ACE2 utilization may arise independently across divergent viral lineages, increasing the likelihood of future zoonotic spillovers6. The RBD’s structural plasticity, evidenced by its ability to accommodate mutations without destabilizing the ACE2 interface, further underscores the adaptive potential of coronaviruses6.

Comparative Affinity with Other Coronaviruses

Functional assays comparing HKU5-CoV-2 to its lineage 1 predecessor revealed enhanced ACE2-binding efficiency in the newer variant, though still lagging behind SARS-CoV-25 6. This incremental adaptation suggests that repeated exposure of bat coronaviruses to human-like receptors—either through natural evolution or intermediate hosts—could gradually enhance their zoonotic fitness5 6.

Contextualizing HKU5-CoV-2 Within the Merbecovirus Family

Relationship to MERS-CoV and Public Health Implications

HKU5-CoV-2 belongs to the merbecovirus species, which includes MERS-CoV—a virus with a 35% fatality rate in humans2 5. Unlike MERS-CoV, which relies on dipeptidyl peptidase-4 (DPP4) receptors, HKU5-CoV-2’s ACE2 tropism places it within a distinct ecological niche but amplifies concerns about its pandemic potential due to ACE2’s widespread expression in human tissues3 5. The study notes that merbecoviruses exhibit remarkable genetic diversity, with four recognized species circulating in bats, hedgehogs, and camels6. This diversity, coupled with their propensity for recombination, positions merbecoviruses as a persistent threat for emergent zoonoses5 6.

Surveillance Gaps and Spillover Pathways

While HKU5-CoV-2 has not yet been detected in human populations, its discovery in Japanese pipistrelle bats (Pipistrellus abramus) highlights surveillance gaps in regions where bat habitats overlap with human settlements3 5. The virus’s broad host range raises the possibility of transmission through intermediate hosts, a pathway implicated in both SARS-CoV-1 and MERS-CoV outbreaks2 5. Researchers emphasize the need for enhanced monitoring of wildlife markets and livestock interfaces in Asia and the Middle East to preempt cross-species transmission3 5.

Institutional Context and Controversies

Wuhan Institute of Virology’s Role in Coronavirus Research

The study’s lead author, Shi Zhengli, directs the Center for Emerging Infectious Diseases at the Wuhan Institute of Virology (WIV), a facility central to global coronavirus research—and controversy1 3 5. The WIV’s extensive collection of bat coronaviruses, including close relatives of SARS-CoV-2, has fueled persistent lab-leak theories regarding the origins of COVID-192 4. While the Chinese government and Shi herself have repeatedly denied these allegations, the U.S. intelligence community’s 2025 assessment cited the WIV’s research as a plausible, though unproven, contributor to the pandemic4 5.

Balancing Scientific Inquiry and Biosafety Concerns

Critics argue that gain-of-function research at the WIV—such as experiments enhancing viral tropism for human receptors—could inadvertently create pandemic pathogens4 5. Proponents counter that such studies are vital for understanding spillover risks and developing countermeasures5 6. The HKU5-CoV-2 study exemplifies this tension: while its findings advance our knowledge of merbecovirus evolution, they also demonstrate the technical capacity to isolate and characterize viruses with high zoonotic potential5 6.

Risk Assessment and Expert Perspectives

Evaluating Pandemic Potential

Dr. Michael Osterholm, an infectious disease expert at the University of Minnesota, characterized public alarm over HKU5-CoV-2 as “overblown,” citing preexisting immunity to SARS-CoV-2 and related viruses in human populations1 4. His assessment aligns with the study’s conclusion that HKU5-CoV-2’s lower ACE2-binding affinity likely restricts its transmissibility compared to SARS-CoV-21 4 6. However, other virologists caution that even modest binding efficiency could suffice for localized outbreaks, particularly in immunologically naïve populations5 6.

Vaccine and Therapeutic Implications

The revelation of HKU5-CoV-2’s ACE2 tropism spurred a transient surge in stock prices for COVID-19 vaccine manufacturers, including Moderna (+5%) and Pfizer (+1%), reflecting market anticipation of renewed demand for coronavirus countermeasures4. However, researchers note that existing mRNA vaccines targeting SARS-CoV-2’s spike protein may offer limited cross-protection against HKU5-CoV-2 due to structural differences in the RBD4 6.

Broader Implications for Pandemic Preparedness

Strengthening Global Surveillance Networks

The discovery of HKU5-CoV-2 underscores the urgency of expanding viral surveillance in bat populations, particularly in Southeast Asia and Africa, where coronavirus diversity is highest3 5. Integrating metagenomic sequencing with ecological studies of bat migration and roosting behavior could improve early detection of spillover-prone variants5 6.

Revisiting the Origins of COVID-19

While the HKU5-CoV-2 study does not directly address the origins of SARS-CoV-2, it reignites debates over the plausibility of natural zoonosis versus research-related incidents4 5. A January 2025 CIA report reiterated low confidence in the lab-leak hypothesis but acknowledged the WIV’s work on SARS-like viruses as a contributing factor4. Concurrently, peer-reviewed studies in Science and Nature continue to support natural origins, emphasizing the evolutionary trajectory of SARS-CoV-2’s furin cleavage site4.

Conclusion: Navigating the Future of Coronavirus Threats

The identification of HKU5-CoV-2 exemplifies the dual-edged nature of coronavirus research: while advancing our understanding of viral evolution, it also exposes vulnerabilities in global biosecurity frameworks. To mitigate future risks, policymakers must balance open scientific collaboration with stringent biosafety protocols, particularly for studies involving potential pandemic pathogens. Concurrently, bolstering public health infrastructure and accelerating universal vaccine platforms remain critical to pandemic preparedness. As bat coronaviruses continue to evolve, the HKU5-CoV-2 discovery serves as a stark reminder of humanity’s interconnectedness with the microbial world—and the perpetual need for vigilance.