Heart-nosed #bat #alphacoronaviruses use #human CEACAM6 to enter #cells

 

Abstract

Identifying viruses with zoonotic potential on the basis of their ability to enter human cells is a critical component of pandemic prediction, prevention and preparedness. Here using a computational approach that retains maximum phylogenetic diversity, we selected an optimal subset of alphacoronavirus spike proteins to screen against broad coronavirus receptor libraries. Most of the selected spike proteins did not use any of the established coronavirus receptors. However, the pseudotyped spike protein of Cardioderma cor (heart-nosed bat) coronavirus KY43 (CcCoV-KY43) could enter human cells. Using a recombinant CcCoV receptor-binding domain (RBD) and a human receptor screening platform, we identified direct interactions with the human CEACAM proteins CEACAM3, CEACAM5 and CEACAM6. Overexpression of human CEACAM6—a protein widely expressed in the human lung—conferred permissivity to otherwise refractory human cells. A crystal structure showed that the RBD binds the amino-terminal IgV-like domain of human CEACAM6. Immune surveillance studies using sera of individuals from the Taveta region of Kenya, where CcCoV-KY43 was identified, did not show significant evidence of recent spillover. Wider characterization of alphacoronaviruses related to CcCoV-KY43 showed that human CEACAM6 is used by two other CcCoVs collected in Kenya. Moreover, there was more restricted nonhuman CEACAM6 tropism for viruses isolated from Rhinolophus bats from Russia and China. Thus, alphacoronaviruses that use CEACAM6 are probably geographically widespread, and viruses from East Africa show potential for transmission to humans.

Source: 

Link: https://www.nature.com/articles/s41586-026-10394-x

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Structural basis for #human #DPP4 #receptor recognition by #MERS-like #coronaviruses 2014-422 and GX2012

 

Abstract

Since its emergence in 2012, Middle East respiratory syndrome coronavirus (MERS-CoV) has posed a significant threat to human health. Recently, novel MERS-like coronaviruses with the potential for cross-species transmission have been identified. In this study, we focused on two newly isolated bat strains with putative health concern: BatCoV/Ii/GD/2014-422 (2014-422) and BtTp-BetaCoV/GX2012 (GX2012). We determined the cryo-EM structures of the spike glycoprotein trimer in the closed state for these two viruses. These structures display a more compact conformation compared to MERS-CoV spike. Biochemical characterization demonstrates that the spike receptor-binding domains (RBDs) of 2014-422 and GX2012 can bind to human dipeptidyl peptidase 4 (hDPP4). To investigate the structural determinants of pseudovirus infection, we solved the cryo-EM structures of 2014-422 RBD-hDPP4 and GX2012 RBD-hDPP4 complexes. The binding mode of the complex is conserved, but the angle of the RBD binding undergoes significant tilting. Detailed structural analysis reveals that an additional residue at position 514 interacts with the N321 glycan in hDPP4, altering the binding angle and thus influencing receptor recognition. These findings offer valuable insights into the receptor utilization of Merbecovirus and provide a structural basis for future surveillance efforts.

Author summary

Two MERS-like coronaviruses, BatCoV/Ii/GD/2014-422 (2014-422) and BtTp-BetaCoV/GX2012 (GX2012), have recently emerged as potential zoonotic threats. In this study, we provide a detailed structural analysis of these two viruses, focusing on their spike proteins and interactions with human Dipeptidyl Peptidase 4 (hDPP4), the receptor used by MERS-CoV. Using cryo-electron microscopy (cryo-EM), we determined high-resolution structures of 2014-422 and GX2012 spike glycoproteins in their closed conformations. Our results show that GX2012 mediates efficient pseudovirus entry into human cells, whereas 2014-422 shows markedly reduced entry efficiency. This difference is linked to structural variations, including a unique residue at position 514 in both viruses that affects the RBD binding angle and receptor recognition. Together, these findings provide key insights into the structural basis of receptor usage by MERS-like coronaviruses and suggest that HKU4r-CoVs may acquire the ability to infect human cells through two evolutionary routes: within bats and through pangolins as intermediate hosts.

Source: 

Link: https://journals.plos.org/plospathogens/article?id=10.1371/journal.ppat.1013792

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