The identification of HKU5-CoV-2 (of the HKU5 lineage 2), a new merbecovirus found in bats of the Zhejiang, Anhui, and Guangxi provinces of China, merits immediate attention. In recent years, coronaviruses have shown their potential for pandemic spread, with SARS-CoV raising significant concern. SARS-CoV-2 caused a global emergency, the COVID-19 pandemic and HKU5-CoV-2 uses the same human cell-surface receptor, angiotensin-converting enzyme 2 (ACE2), as a portal to host cellular entry as SARS-CoV-2 and is of concern in terms of its potential for zoonotic transmission.
SARS-CoV-2 caused a global emergency, the COVID-19 pandemic and HKU5-CoV-2 uses the same human cell-surface receptor, angiotensin-converting enzyme 2 (ACE2), as a portal to host cellular entry as SARS-CoV-2 and is of concern in terms of its potential for zoonotic transmission.
Additionally, HKU5-Co V-2 is part of the same family as other coronaviruses that are known to infect human cells, such as Middle East Respiratory Syndrome (MERS-CoV) [4]. It has a genetically sequenced structure highly like zoonotic coronaviruses, with adaptive mutations that enhance human ACE2 receptor binding. This is of concern as there is a risk that HKU5-CoV-2 could spill over into humans. However, with over 3000 bat coronaviruses in existence, all have the potential to evolve into human pathogens, though this does not mean that they will lead to significant health issues in humans [5]. Thus far, no HKU5-CoV-2 human cases have been reported, but the adaptability of these viruses implies the need for further research. The experience of history is that coronaviruses that emanate from bats have recombined and evolved towards strains that target humans. Identifying the new HKU5-CoV-2 virus in several provinces further implicates monitoring channels for wildlife transmission to human vectors.
Structural studies show that the virus employs a mechanism similar to SARS-CoV-2, where the spike (S) protein is conformationally modified to increase receptor affinity. Studies have documented mutations at residue 310, which overlap with important ACE2-binding sites in SARS-CoV-2 and NL63, indicating an adaptation for human receptor interaction. The binding is enhanced by hydrogen bonding and electrostatic interactions between viral spike protein and ACE2 residues, a characteristic common with SARS-CoV-2 but different from other merbecoviruses.
Moreover, HKU5-CoV-2 harbours adaptive mutations in the furin cleavage site, which is critical in the penetration of the host cell and increasing the infectivity. This cleavage site enables the virus to fuse efficiently with human cell membranes, further increasing its spillover potential. These findings suggest that although HKU5-CoV-2 is currently restricted to its bat host, it retains the molecular potential to bridge to the human host and, thus, is a potential public health concern [6] (see Table 1).
The circulation of HKU5-CoV-2 in multiple bat species across distinct geographic regions indicates that this virus is not a recent emergence but a widespread, previously unrecognised viral reservoir. The co-circulation of genetically distinct coronaviruses in bat populations will likely lead to inter-viral recombination events that increase transmissibility or virulence. Surveillance may focus on the early identification of such events of viral recombination, which may themselves follow cross-species transfer. However, as HKU5-CoV-2 has 57 per cent of its genes, specifically the S gene and S2 region, genetically identical to those human pathogenic coronaviruses, aggressive surveillance protocols should be implemented to prevent a potential event for transmitting this virus to humans.
HKU5-CoV-2 has significant public health implications. Understanding the host range and the transmission dynamics of HKU5-CoV-2 is crucial for identifying emerging hazards before they emerge. Rather than focusing surveillance on bat reservoirs, it should also span livestock and human populations in regions where the virus has been identified to flag potential spillover events early. Multi-level surveillance strategies with early detection are needed, integrating genomic sequencing, serological studies, and real-time environmental sampling. Metagenomic sequencing of bat populations could identify emerging viral strains before their infection of human hosts.
Serological surveillance among at-risk human populations, particularly those engaged in wildlife trade or animal husbandry, may be facilitated early. In addition, wastewater-based epidemiology has helped monitor viral circulation among populations and can potentially be an early warning system for new coronaviruses. Advanced point-of-care diagnostic technology, including CRISPR-based detection platforms, can facilitate improved rapid detection of new viral strains before widespread transmission. Further, artificial intelligence-driven predictive modelling can track viral evolutionary trends and guide proactive mitigation efforts. Global collaborative efforts, including One Health surveillance programs, must be enhanced for cross-sector data exchange and early intervention responses.
The case of HKU5-CoV-2 serves as a reminder of the ongoing risk posed by coronaviruses in bats and their potential zoonotic transmissibility. Although no human cases have been reported, the virus’s ability to use human ACE2 receptors raises significant concerns. Continuous surveillance and global cooperation are crucial to mitigate the risk of a potential human outbreak leading to a pandemic.
Vasso Apoostolopoulos, Professor of Immunology and a Vice-Chancellor’s Distinguished Fellow, Victoria University, leads the Immunology and Translational Research Group and is the Program Director, Immunology, at the Australian Institute for Musculoskeletal Science.
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