HKU25 clade #MERS-related #coronaviruses use #ACE2 as a functional #receptor

 

Abstract

Dipeptidyl peptidase-4 (DPP4) is an established receptor for Middle East respiratory syndrome-related coronaviruses (MERSr-CoVs), while recent studies have identified angiotensin-converting enzyme 2 (ACE2) usage in multiple merbecovirus clades. Yet, receptor usage of many genetically diverse bat MERSr-CoVs remains unclear. Here we show that broadly distributed HKU25 clade merbecoviruses use ACE2, rather than DPP4, as their receptor. Cryo-electron microscopy revealed that HsItaly2011 and VsCoV-a7 strains engage ACE2 similarly to HKU5 but with remodelled interfaces and distinct orthologue selectivity, suggesting a shared evolutionary origin of ACE2 recognition. EjCoV-3, a close relative of the DPP4-using BtCoV422, showed broad multi-species ACE2 tropism and preadaptation to human ACE2. Several ACE2 glycans and residues within or near the binding interface were identified as determinants of orthologue selectivity. These viruses remain sensitive to several broadly neutralizing antibodies and entry inhibitors, indicating potential countermeasures for future outbreaks. These findings highlight the versatility of ACE2 as a functional receptor for diverse coronaviruses.

Source: Nature Microbiology, https://www.nature.com/articles/s41564-025-02152-y

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Identification and characterization of novel #bat #coronaviruses in #Spain

Abstract

The zoonotic transmission of bat coronaviruses poses a threat to human health. However, the diversity of bat-borne coronaviruses remains poorly characterized in many geographical areas. Here, we recovered eight coronavirus genomes by performing a metagenomic analysis of fecal samples from hundreds of individual bats captured in Spain, a country with high bat diversity. Three of these genomes corresponded to potentially novel coronavirus species belonging to the alphacoronavirus genus. Phylogenetic analyses revealed that some of these viruses are closely related to coronaviruses previously described in bats from other countries, suggesting a shared viral reservoir worldwide. Using viral pseudotypes, we investigated the receptor usage of the identified viruses and found that one of them can use human ACE2, albeit with lower affinity than SARS-CoV-2. However, the receptor usage of the other viruses remains unknown. This study broadens our understanding of coronavirus diversity and identifies research priorities for the prevention of zoonotic viral outbreaks.

Author summary

Bats carry many different viruses, some of which can infect humans. Among these, bat coronaviruses are of particular concern. To be better prepared for future pandemics, it is important to understand how many of these viruses exist and their ability to infect different hosts. However, research in this area has often focused on certain parts of the world, while other regions remain underexplored. Spain has a rich diversity of bats, but very few studies have looked for coronaviruses in bats from the Iberian Peninsula. Here, we used viral metagenomics to test for the presence of coronaviruses in more than 200 bat samples collected across Spain. We identified eight coronavirus genomes, three of which may constitute new species. We also examined how closely related they are to previously known viruses, and whether they can use the same cellular receptors as known coronaviruses. Notably, we found that one of the viruses could use human ACE2, the SARS-CoV-2 receptor. Our findings reveal that bats in Spain host a diverse range of coronaviruses, including some that could potentially infect humans. This highlights the importance of studying coronavirus diversity more broadly worldwide.

Source: PLoS Pathogens, https://journals.plos.org/plospathogens/article?id=10.1371/journal.ppat.1013371

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HKU5 #bat #merbecoviruses engage bat and #mink #ACE2 as entry #receptors

Abstract

Identifying receptors for bat coronaviruses is critical for spillover risk assessment, countermeasure development, and pandemic preparedness. While Middle East respiratory syndrome coronavirus (MERS-CoV) uses DPP4 for entry, the receptors of many MERS-related betacoronaviruses remain unknown. The bat merbecovirus HKU5 was previously shown to have an entry restriction in human cells. Using both pseudotyped and full-length virus, we show that HKU5 uses Pipistrellus abramus bat ACE2 but not human ACE2 or DPP4 as a receptor. Cryo-electron microscopy analysis of the virus-receptor complex and structure-guided mutagenesis reveal a spike and ACE2 interaction that is distinct from other ACE2-using coronaviruses. MERS-CoV vaccine sera poorly neutralize HKU5 informing pan-merbecovirus vaccine design. Notably, HKU5 can also engage American mink and stoat ACE2, revealing mustelids as potential intermediate hosts. These findings highlight the versatility of merbecovirus receptor use and underscore the need for continued surveillance of bat and mustelid species.

Source: Nature Communications, https://www.nature.com/articles/s41467-025-61583-7

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A #MERS-CoV-like #mink #coronavirus uses #ACE2 as entry receptor

Abstract

Despite accumulating evidence that bat-derived coronaviruses often require intermediate hosts to facilitate transmission to humans1, the potential role of fur animals in zoonotic coronavirus spillovers has largely been overlooked2. Here we report the isolation and characterization of a novel mink respiratory coronavirus (MRCoV) from farmed minks with pneumonia. Notably, MRCoV uses angiotensin-converting enzyme 2 (ACE2) as a receptor and can infect mink, bat, monkey, and human cells. Cryo-electron microscopy analysis revealed that the MRCoV receptor-binding domain (RBD) binds to the same interface on ACE2 receptors as severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) RBD, despite exhibiting notable structural differences. We identify the key determinants on ACE2 and MRCoV RBD that confer efficient binding. HKU5-33S, a bat coronavirus closely related to MRCoV, utilizes ACE2 of bat Pipistrellus abramus and requires only two amino acid substitutions to adapt to mink ACE2. Furthermore, SARS-CoV-2 protease and polymerase inhibitors potently block MRCoV infection, indicating a potential therapeutic strategy. Collectively, these findings enhance the understanding of coronavirus receptor dynamics and highlight their zoonotic potential. Given the risks posed by fur farms as reservoirs for emerging pathogens, our study underscores the urgent need for enhanced surveillance to mitigate future coronavirus outbreaks.

Source: Nature, https://www.nature.com/articles/s41586-025-09007-w

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#Bat-infecting #merbecovirus HKU5-CoV #lineage 2 can use #human #ACE2 as a cell entry receptor

Highlights

• A distinct HKU5 coronavirus lineage (HKU5-CoV-2) is discovered in bats

• Bat HKU5-CoV-2 uses human ACE2 receptor and ACE2 orthologs from multiple species

• Bat HKU5-CoV-2 RBD engages human ACE2 with a distinct binding mode from other CoVs

• Bat HKU5-CoV-2 was isolated and infect human-ACE2-expressing cells

Summary

Merbecoviruses comprise four viral species with remarkable genetic diversity: MERS-related coronavirus, Tylonycterisbat coronavirus HKU4, Pipistrellusbat coronavirus HKU5, and Hedgehog coronavirus 1. However, the potential human spillover risk of animal merbecoviruses remains to be investigated. Here, we reported the discovery of HKU5-CoV lineage 2 (HKU5-CoV-2) in bats that efficiently utilize human angiotensin-converting enzyme 2 (ACE2) as a functional receptor and exhibits a broad host tropism. Cryo-EM analysis of HKU5-CoV-2 receptor-binding domain (RBD) and human ACE2 complex revealed an entirely distinct binding mode compared with other ACE2-utilizing merbecoviruses with RBD footprint largely shared with ACE2-using sarbecoviruses and NL63. Structural and functional analyses indicate that HKU5-CoV-2 has a better adaptation to human ACE2 than lineage 1 HKU5-CoV. Authentic HKU5-CoV-2 infected human ACE2-expressing cell lines and human respiratory and enteric organoids. This study reveals a distinct lineage of HKU5-CoVs in bats that efficiently use human ACE2 and underscores their potential zoonotic risk.

Source: Cell, https://www.cell.com/cell/abstract/S0092-8674(25)00144-8?_returnURL=https%3A%2F%2Flinkinghub.elsevier.com%2Fretrieve%2Fpii%2FS0092867425001448%3Fshowall%3Dtrue

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