Skip to main content

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

Image
By G.M.

 


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

____

Labels:

Comments

Post a Comment

Popular posts from this blog

#Neuroinvasive #Oropouche virus in a patient with #HIV from extra-Amazonian #Brazil

By G.M.
{Excerpt} A novel reassortant Oropouche virus (OROV) lineage (with medium [M], large [L], and small [S] RNA segments : M1L2S2) has driven Brazil's largest and most geographically widespread OROV epidemic , expanding beyond the endemic Amazon basin to establish local transmission across multiple Brazilian states and other previously unaffected Latin American countries . The rapid spread of this lineage underscores its evolutionary potential and reinforces its significance as a public health threat .1 Similar to chikungunya and Zika viruses, expanding arboviruses can exhibit unexpected clinical and epidemiological shifts , including vertical transmissions , neuroinvasive effects, and potentially fatal outcomes.2–4 Although OROV typically causes self-limited febrile illness, accumulating clinical and experimental evidence suggests neurotropic potential .5 This Correspondence describes the first confirmed case of neuroinvasive OROV infection caused by the emergent M1L2S2 lineage in ext...
Post a Comment
Read more »

No evidence of immune #exhaustion after repeated #SARS-CoV-2 #vaccination in vulnerable and healthy populations

By G.M.
Abstract Frequent SARS-CoV-2 vaccination in vulnerable populations has raised concerns that this may contribute to T cell exhaustion , which could negatively affect the quality of immune protection. Herein, we examined the impact of repeated SARS-CoV-2 vaccination on T cell phenotypic and functional exhaustion in frail older adults in long-term care (n = 23), individuals on immunosuppressive drugs (n = 10), and healthy adults (n = 43), in Canada . Spike-specific CD4+ and CD8+ T cell levels did not decline in any cohort following repeated SARS-CoV-2 vaccination, nor did the expression of exhaustion markers on spike-specific or total T cells increase. T cell production of multiple cytokines (i.e. polyfunctionality) in response to the spike protein of SARS-CoV-2 did not decline in any cohort following repeated vaccination. None of the cohorts displayed elevated levels of terminally differentiated T cells following multiple SARS-CoV-2 vaccinations. Thus, repeated SARS-CoV-2 vaccination was...
Post a Comment
Read more »

Chimeric #hemagglutinin and #M2 #mRNA #vaccine for broad #influenza subtype protection

By G.M.
Abstract Since multiple and unpredicted influenza viruses cause seasonal epidemics and even high-risk pandemics , developing a universal influenza vaccine is essential to provide broad protection against various influenza subtypes. Combined with the mRNA lipid nanoparticle-encapsulated (mRNA-LNP) vaccine platform and chimeric immunogen strategy , we developed a novel cocktail mRNA vaccine encoding chimeric HAs (cH5/1-BV, cH7/3) and intact M2 (termed Fluaxe), which confers broad protection against major circulating IAVs and IBVs , as well as highly pathogenic avian influenza . Two-dose intramuscular immunization of Fluaxe in mice elicited cross-reactive neutralizing antibodies , T cell responses, and long-lived immunity, resulting in robust protection against multiple lethal influenza virus infections and severe acute lung injuries . In particular, intramuscular administration stimulated systemic immunity together with a prominent lung tropism of memory cells . Moreover, Fluaxe immuniza...
Post a Comment
Read more »