Following the outbreak of coronavirus disease 2019(COVID-19),several severe acute respiratory syndrome coronavirus 2(SARS-CoV-2)-related coronaviruses have been discovered.Previous research has identified a novel line...Following the outbreak of coronavirus disease 2019(COVID-19),several severe acute respiratory syndrome coronavirus 2(SARS-CoV-2)-related coronaviruses have been discovered.Previous research has identified a novel lineage of SARS-CoV-2-related CoVs in bats,including RsYN04,which recognizes human angiotensin-converting enzyme 2(ACE2)and thus poses a potential threat to humans.Here,we screened the binding of the RsYN04receptor-binding domain(RBD)to ACE2 orthologs from 52animal species and found that the virus showed a narrower ACE2-binding spectrum than SARS-CoV-2.However,the presence of the T484W mutation in the RsYN04 RBD broadened its range.We also evaluated 44 SARS-CoV-2antibodies targeting seven epitope communities in the SARS-CoV-2 RBD,together with serum obtained from COVID-19 convalescents and vaccinees,to determine their cross-reaction against RsYN04.Results showed that no antibodies,except for the RBD-6 and RBD-7 classes,bound to the RsYN04 RBD,indicating substantial immune differences from SARS-CoV-2.Furthermore,the structure of the RsYN04 RBD in complex with cross-reactive antibody S43 in RBD-7 revealed a potently broad epitope for the development of therapeutics and vaccines.Our findings suggest RsYN04 and other viruses belonging to the same clade have the potential to infect several species,including humans,highlighting the necessity for viral surveillance and development of broad anticoronavirus countermeasures.展开更多
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
基金supported by the National Key R&D Program of China (2022YFC2303403)National Natural Science Foundation of China (82225021)supported by the Chinese Academy of Sciences (YSBR-010 and Y2022037)。
文摘Following the outbreak of coronavirus disease 2019(COVID-19),several severe acute respiratory syndrome coronavirus 2(SARS-CoV-2)-related coronaviruses have been discovered.Previous research has identified a novel lineage of SARS-CoV-2-related CoVs in bats,including RsYN04,which recognizes human angiotensin-converting enzyme 2(ACE2)and thus poses a potential threat to humans.Here,we screened the binding of the RsYN04receptor-binding domain(RBD)to ACE2 orthologs from 52animal species and found that the virus showed a narrower ACE2-binding spectrum than SARS-CoV-2.However,the presence of the T484W mutation in the RsYN04 RBD broadened its range.We also evaluated 44 SARS-CoV-2antibodies targeting seven epitope communities in the SARS-CoV-2 RBD,together with serum obtained from COVID-19 convalescents and vaccinees,to determine their cross-reaction against RsYN04.Results showed that no antibodies,except for the RBD-6 and RBD-7 classes,bound to the RsYN04 RBD,indicating substantial immune differences from SARS-CoV-2.Furthermore,the structure of the RsYN04 RBD in complex with cross-reactive antibody S43 in RBD-7 revealed a potently broad epitope for the development of therapeutics and vaccines.Our findings suggest RsYN04 and other viruses belonging to the same clade have the potential to infect several species,including humans,highlighting the necessity for viral surveillance and development of broad anticoronavirus countermeasures.
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.
