Foxes are susceptible to SARS-CoV-2 in laboratory settings,and there have also been reports of natural infections of both SARS-CoV and SARS-CoV-2 in foxes.In this study,we assessed the binding capacities of fox ACE2 t...Foxes are susceptible to SARS-CoV-2 in laboratory settings,and there have also been reports of natural infections of both SARS-CoV and SARS-CoV-2 in foxes.In this study,we assessed the binding capacities of fox ACE2 to important sarbecoviruses,including SARS-CoV,SARS-CoV-2,and animal-origin SARS-CoV-2 related viruses.Our findings demonstrated that fox ACE2 exhibits broad binding capabilities to receptor-binding domains(RBDs)of sarbecoviruses.We further determined the cryo-EM structures of fox ACE2 complexed with RBDs of SARS-CoV,SARS-CoV-2 prototype(PT),and Omicron BF.7.Through structural analysis,we identified that the K417 mutation can weaken the ability of SARS-CoV-2 sub-variants to bind to fox ACE2,thereby reducing the susceptibility of foxes to SARS-CoV-2 sub-variants.In addition,the Y498 residue in the SARS-CoV RBD plays a crucial role in forming a vital cation-πinteraction with K353 in the fox ACE2 receptor.This interaction is the primary determinant for the higher affinity of the SARS-CoV RBD compared to that of the SARS-CoV-2 PT RBD.These results indicate that foxes serve as potential hosts for numerous sarbecoviruses,highlighting the critical importance of surveillance efforts.展开更多
Major outbreaks of severe acute respiratory syndrome(SARS)and coronavirus disease 2019(COVID-19),together with the continuous risk of zoonotic spillover of animal sarbecoviruses,underscore the urgent need for vaccines...Major outbreaks of severe acute respiratory syndrome(SARS)and coronavirus disease 2019(COVID-19),together with the continuous risk of zoonotic spillover of animal sarbecoviruses,underscore the urgent need for vaccines that confer broad protection across the sarbecovirus subgenus.Current immunogen selection strategies for pansarbecovirus vaccine development predominantly rely on phylogenetic or spike sequence conservation analyses,which often fail to accurately predict the breadth of cross-neutralization.To overcome this limitation,we systematically evaluated cross-neutralization profiles among 25 representative sarbecoviruses from clades 1 and 3 via guinea pig antisera individually raised against full-length spike proteins in pseudovirus neutralization assays while excluding clade 2 viruses lacking known receptor usage.Neutralization profiling revealed four distinct immunogenic clusters that diverged from traditional phylogenetic relationships.Antisera induced by the palm civet-derived SARS-CoV-1 strain SZ1 broadly neutralized all clade 1a viruses,whereas full coverage of clade 1b viruses required at least two distinct immunogens.Remarkably,sera elicited by multiple clade 1 immunogens also neutralized clade 3 viruses despite no prior exposure to clade 3 antigens.Guided by these findings,we proposed a minimal trivalent immunogen combination—SZ1,SARS-CoV-2,and PCoV-GX—that elicited broad neutralization against both clade 1 and clade 3.This rational approach eliminates the need for additional clade 3-specific antigens and provides a preclinical framework for developing next-generation pansarbecovirus vaccines.展开更多
基金supported by the National Key R&D Program of China(2022YFC2303401,2021YFA1300803)National Natural Science Foundation of China(32122008)+2 种基金supported by Young Elite Scientists Sponsorship Program by CAST(2021QNRC001)fellowships from the China Postdoctoral Science Foundation(2022T150688)the Postdoctoral Science Foundation of China(2021M700161).
文摘Foxes are susceptible to SARS-CoV-2 in laboratory settings,and there have also been reports of natural infections of both SARS-CoV and SARS-CoV-2 in foxes.In this study,we assessed the binding capacities of fox ACE2 to important sarbecoviruses,including SARS-CoV,SARS-CoV-2,and animal-origin SARS-CoV-2 related viruses.Our findings demonstrated that fox ACE2 exhibits broad binding capabilities to receptor-binding domains(RBDs)of sarbecoviruses.We further determined the cryo-EM structures of fox ACE2 complexed with RBDs of SARS-CoV,SARS-CoV-2 prototype(PT),and Omicron BF.7.Through structural analysis,we identified that the K417 mutation can weaken the ability of SARS-CoV-2 sub-variants to bind to fox ACE2,thereby reducing the susceptibility of foxes to SARS-CoV-2 sub-variants.In addition,the Y498 residue in the SARS-CoV RBD plays a crucial role in forming a vital cation-πinteraction with K353 in the fox ACE2 receptor.This interaction is the primary determinant for the higher affinity of the SARS-CoV RBD compared to that of the SARS-CoV-2 PT RBD.These results indicate that foxes serve as potential hosts for numerous sarbecoviruses,highlighting the critical importance of surveillance efforts.
基金supported by the Natural Science Foundation of China(grant no.82172244)the Major Project of Guangzhou National Laboratory(GZNL2024A01019).
文摘Major outbreaks of severe acute respiratory syndrome(SARS)and coronavirus disease 2019(COVID-19),together with the continuous risk of zoonotic spillover of animal sarbecoviruses,underscore the urgent need for vaccines that confer broad protection across the sarbecovirus subgenus.Current immunogen selection strategies for pansarbecovirus vaccine development predominantly rely on phylogenetic or spike sequence conservation analyses,which often fail to accurately predict the breadth of cross-neutralization.To overcome this limitation,we systematically evaluated cross-neutralization profiles among 25 representative sarbecoviruses from clades 1 and 3 via guinea pig antisera individually raised against full-length spike proteins in pseudovirus neutralization assays while excluding clade 2 viruses lacking known receptor usage.Neutralization profiling revealed four distinct immunogenic clusters that diverged from traditional phylogenetic relationships.Antisera induced by the palm civet-derived SARS-CoV-1 strain SZ1 broadly neutralized all clade 1a viruses,whereas full coverage of clade 1b viruses required at least two distinct immunogens.Remarkably,sera elicited by multiple clade 1 immunogens also neutralized clade 3 viruses despite no prior exposure to clade 3 antigens.Guided by these findings,we proposed a minimal trivalent immunogen combination—SZ1,SARS-CoV-2,and PCoV-GX—that elicited broad neutralization against both clade 1 and clade 3.This rational approach eliminates the need for additional clade 3-specific antigens and provides a preclinical framework for developing next-generation pansarbecovirus vaccines.
