Your browser doesn't support javascript.
Show: 20 | 50 | 100
Results 1 - 10 de 10
Filter
1.
Nat Commun ; 13(1): 3547, 2022 06 21.
Article in English | MEDLINE | ID: covidwho-1900489

ABSTRACT

The origin and host range of SARS-CoV-2, the causative agent of coronavirus disease 2019 (COVID-19), are important scientific questions as they might provide insight into understanding of the potential future spillover to infect humans. Here, we tested the binding between equine angiotensin converting enzyme 2 (eqACE2) and the receptor binding domains (RBDs) of SARS-CoV, SARS-CoV-2 prototype (PT) and variant of concerns (VOCs), as well as their close relatives bat-origin coronavirus (CoV) RaTG13 and pangolin-origin CoVs GX/P2V/2017 and GD/1/2019. We also determined the crystal structures of eqACE2/RaTG13-RBD, eqACE2/SARS-CoV-2 PT-RBD and eqACE2/Omicron BA.1-RBD. We identified S494 of SARS-COV-2 PT-RBD as an important residue in the eqACE2/SARS-COV-2 PT-RBD interaction and found that N501Y, the commonly recognized enhancing mutation, attenuated the binding affinity with eqACE2. Our work demonstrates that horses are potential targets for SARS-CoV-2 and highlights the importance of continuous surveillance on SARS-CoV-2 and related CoVs to prevent spillover events.


Subject(s)
Angiotensin-Converting Enzyme 2 , COVID-19 , Animals , Horses , Peptidyl-Dipeptidase A/metabolism , Protein Binding , SARS-CoV-2/genetics , Spike Glycoprotein, Coronavirus/metabolism
2.
Immunity ; 55(8): 1501-1514.e3, 2022 Aug 09.
Article in English | MEDLINE | ID: covidwho-1885835

ABSTRACT

SARS-CoV-2 Omicron variant has presented significant challenges to current antibodies and vaccines. Herein, we systematically compared the efficacy of 50 human monoclonal antibodies (mAbs), covering the seven identified epitope classes of the SARS-CoV-2 RBD, against Omicron sub-variants BA.1, BA.1.1, BA.2, and BA.3. Binding and pseudovirus-based neutralizing assays revealed that 37 of the 50 mAbs lost neutralizing activities, whereas the others displayed variably decreased activities against the four Omicron sub-variants. BA.2 was found to be more sensitive to RBD-5 antibodies than the other sub-variants. Furthermore, a quaternary complex structure of BA.1 RBD with three mAbs showing different neutralizing potencies against Omicron provided a basis for understanding the immune evasion of Omicron sub-variants and revealed the lack of G446S mutation accounting for the sensitivity of BA.2 to RBD-5 mAbs. Our results may guide the application of the available mAbs and facilitate the development of universal therapeutic antibodies and vaccines against COVID-19.


Subject(s)
Antibodies, Neutralizing , COVID-19 , Antibodies, Monoclonal , Antibodies, Viral , COVID-19 Vaccines , Humans , Membrane Glycoproteins , SARS-CoV-2 , Spike Glycoprotein, Coronavirus , Viral Envelope Proteins
3.
Innovation (N Y) ; 3(2): 100206, 2022 Mar 29.
Article in English | MEDLINE | ID: covidwho-1799659
5.
China CDC Wkly ; 3(46): 967-972, 2021 Nov 12.
Article in English | MEDLINE | ID: covidwho-1513532

ABSTRACT

INTRODUCTION: Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) is a recently emergent coronavirus of natural origin and caused the coronavirus disease (COVID-19) pandemic. The study of its natural origin and host range is of particular importance for source tracing, monitoring of this virus, and prevention of recurrent infections. One major approach is to test the binding ability of the viral receptor gene ACE2 from various hosts to SARS-CoV-2 spike protein, but it is time-consuming and labor-intensive to cover a large collection of species. METHODS: In this paper, we applied state-of-the-art machine learning approaches and created a pipeline reaching >87% accuracy in predicting binding between different ACE2 and SARS-CoV-2 spike. RESULTS: We further validated our prediction pipeline using 2 independent test sets involving >50 bat species and achieved >78% accuracy. A large-scale screening of 204 mammal species revealed 144 species (or 61%) were susceptible to SARS-CoV-2 infections, highlighting the importance of intensive monitoring and studies in mammalian species. DISCUSSION: In short, our study employed machine learning models to create an important tool for predicting potential hosts of SARS-CoV-2 and achieved the highest precision to our knowledge in experimental validation. This study also predicted that a wide range of mammals were capable of being infected by SARS-CoV-2.

6.
Cell ; 184(13): 3438-3451.e10, 2021 06 24.
Article in English | MEDLINE | ID: covidwho-1275185

ABSTRACT

Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) has been spreading worldwide, causing a global pandemic. Bat-origin RaTG13 is currently the most phylogenetically related virus. Here we obtained the complex structure of the RaTG13 receptor binding domain (RBD) with human ACE2 (hACE2) and evaluated binding of RaTG13 RBD to 24 additional ACE2 orthologs. By substituting residues in the RaTG13 RBD with their counterparts in the SARS-CoV-2 RBD, we found that residue 501, the major position found in variants of concern (VOCs) 501Y.V1/V2/V3, plays a key role in determining the potential host range of RaTG13. We also found that SARS-CoV-2 could induce strong cross-reactive antibodies to RaTG13 and identified a SARS-CoV-2 monoclonal antibody (mAb), CB6, that could cross-neutralize RaTG13 pseudovirus. These results elucidate the receptor binding and host adaption mechanisms of RaTG13 and emphasize the importance of continuous surveillance of coronaviruses (CoVs) carried by animal reservoirs to prevent another spillover of CoVs.


Subject(s)
Angiotensin-Converting Enzyme 2/metabolism , Binding Sites/physiology , COVID-19/metabolism , Chiroptera/virology , SARS-CoV-2/pathogenicity , Amino Acid Sequence , Animals , Antibodies, Monoclonal/immunology , COVID-19/immunology , Chiroptera/immunology , Chiroptera/metabolism , Host Specificity/immunology , Humans , Phylogeny , Protein Binding/physiology , Receptors, Virus/metabolism , SARS-CoV-2/immunology , Sequence Alignment
7.
EMBO J ; 40(16): e107786, 2021 08 16.
Article in English | MEDLINE | ID: covidwho-1239217

ABSTRACT

Pangolins have been suggested as potential reservoir of zoonotic viruses, including SARS-CoV-2 causing the global COVID-19 outbreak. Here, we study the binding of two SARS-CoV-2-like viruses isolated from pangolins, GX/P2V/2017 and GD/1/2019, to human angiotensin-converting enzyme 2 (hACE2), the receptor of SARS-CoV-2. We find that the spike protein receptor-binding domain (RBD) of pangolin CoVs binds to hACE2 as efficiently as the SARS-CoV-2 RBD in vitro. Furthermore, incorporation of pangolin CoV RBDs allows entry of pseudotyped VSV particles into hACE2-expressing cells. A screen for binding of pangolin CoV RBDs to ACE2 orthologs from various species suggests a broader host range than that of SARS-CoV-2. Additionally, cryo-EM structures of GX/P2V/2017 and GD/1/2019 RBDs in complex with hACE2 show their molecular binding in modes similar to SARS-CoV-2 RBD. Introducing the Q498H substitution found in pangolin CoVs into the SARS-CoV-2 RBD expands its binding capacity to ACE2 homologs of mouse, rat, and European hedgehog. These findings suggest that these two pangolin CoVs may infect humans, highlighting the necessity of further surveillance of pangolin CoVs.


Subject(s)
Angiotensin-Converting Enzyme 2/metabolism , Betacoronavirus/physiology , Pangolins/virology , SARS-CoV-2/physiology , Spike Glycoprotein, Coronavirus/chemistry , Spike Glycoprotein, Coronavirus/metabolism , Amino Acid Substitution , Angiotensin-Converting Enzyme 2/chemistry , Animals , Binding Sites , HEK293 Cells , Hedgehogs/virology , Host Specificity , Humans , Mice , Models, Molecular , Phylogeny , Protein Binding , Protein Conformation , Rats , Spike Glycoprotein, Coronavirus/genetics , Virus Internalization
8.
Proc Natl Acad Sci U S A ; 118(1)2021 01 05.
Article in English | MEDLINE | ID: covidwho-1066044

ABSTRACT

The coronavirus disease 2019 (COVID-19) pandemic caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) has emerged as a major threat to global health. Although varied SARS-CoV-2-related coronaviruses have been isolated from bats and SARS-CoV-2 may infect bat, the structural basis for SARS-CoV-2 to utilize the human receptor counterpart bat angiotensin-converting enzyme 2 (bACE2) for virus infection remains less understood. Here, we report that the SARS-CoV-2 spike protein receptor binding domain (RBD) could bind to bACE2 from Rhinolophus macrotis (bACE2-Rm) with substantially lower affinity compared with that to the human ACE2 (hACE2), and its infectivity to host cells expressing bACE2-Rm was confirmed with pseudotyped SARS-CoV-2 virus and SARS-CoV-2 wild virus. The structure of the SARS-CoV-2 RBD with the bACE2-Rm complex was determined, revealing a binding mode similar to that of hACE2. The analysis of binding details between SARS-CoV-2 RBD and bACE2-Rm revealed that the interacting network involving Y41 and E42 of bACE2-Rm showed substantial differences with that to hACE2. Bats have extensive species diversity and the residues for RBD binding in bACE2 receptor varied substantially among different bat species. Notably, the Y41H mutant, which exists in many bats, attenuates the binding capacity of bACE2-Rm, indicating the central roles of Y41 in the interaction network. These findings would benefit our understanding of the potential infection of SARS-CoV-2 in varied species of bats.


Subject(s)
Angiotensin-Converting Enzyme 2 , COVID-19/genetics , COVID-19/metabolism , Chiroptera , SARS-CoV-2 , Amino Acid Substitution , Angiotensin-Converting Enzyme 2/chemistry , Angiotensin-Converting Enzyme 2/genetics , Angiotensin-Converting Enzyme 2/metabolism , Animals , COVID-19/epidemiology , Chiroptera/genetics , Chiroptera/metabolism , Chiroptera/virology , HEK293 Cells , Humans , Mutation, Missense , Pandemics , Protein Binding , Protein Domains , SARS-CoV-2/chemistry , SARS-CoV-2/genetics , SARS-CoV-2/metabolism , Species Specificity
9.
Proc Natl Acad Sci U S A ; 118(1)2021 01 05.
Article in English | MEDLINE | ID: covidwho-990135

ABSTRACT

The coronavirus disease 2019 (COVID-19) pandemic caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) has emerged as a major threat to global health. Although varied SARS-CoV-2-related coronaviruses have been isolated from bats and SARS-CoV-2 may infect bat, the structural basis for SARS-CoV-2 to utilize the human receptor counterpart bat angiotensin-converting enzyme 2 (bACE2) for virus infection remains less understood. Here, we report that the SARS-CoV-2 spike protein receptor binding domain (RBD) could bind to bACE2 from Rhinolophus macrotis (bACE2-Rm) with substantially lower affinity compared with that to the human ACE2 (hACE2), and its infectivity to host cells expressing bACE2-Rm was confirmed with pseudotyped SARS-CoV-2 virus and SARS-CoV-2 wild virus. The structure of the SARS-CoV-2 RBD with the bACE2-Rm complex was determined, revealing a binding mode similar to that of hACE2. The analysis of binding details between SARS-CoV-2 RBD and bACE2-Rm revealed that the interacting network involving Y41 and E42 of bACE2-Rm showed substantial differences with that to hACE2. Bats have extensive species diversity and the residues for RBD binding in bACE2 receptor varied substantially among different bat species. Notably, the Y41H mutant, which exists in many bats, attenuates the binding capacity of bACE2-Rm, indicating the central roles of Y41 in the interaction network. These findings would benefit our understanding of the potential infection of SARS-CoV-2 in varied species of bats.


Subject(s)
Angiotensin-Converting Enzyme 2 , COVID-19/genetics , COVID-19/metabolism , Chiroptera , SARS-CoV-2 , Amino Acid Substitution , Angiotensin-Converting Enzyme 2/chemistry , Angiotensin-Converting Enzyme 2/genetics , Angiotensin-Converting Enzyme 2/metabolism , Animals , COVID-19/epidemiology , Chiroptera/genetics , Chiroptera/metabolism , Chiroptera/virology , HEK293 Cells , Humans , Mutation, Missense , Pandemics , Protein Binding , Protein Domains , SARS-CoV-2/chemistry , SARS-CoV-2/genetics , SARS-CoV-2/metabolism , Species Specificity
10.
Cell Discov ; 6: 68, 2020.
Article in English | MEDLINE | ID: covidwho-817184

ABSTRACT

Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), the causative agent of the recent pandemic COVID-19, is reported to have originated from bats, with its intermediate host unknown to date. Here, we screened 26 animal counterparts of the human ACE2 (hACE2), the receptor for SARS-CoV-2 and SARS-CoV, and found that the ACE2s from various species, including pets, domestic animals and multiple wild animals, could bind to SARS-CoV-2 receptor binding domain (RBD) and facilitate the transduction of SARS-CoV-2 pseudovirus. Comparing to SARS-CoV-2, SARS-CoV seems to have a slightly wider range in choosing its receptor. We further resolved the cryo-electron microscopy (cryo-EM) structure of the cat ACE2 (cACE2) in complex with the SARS-CoV-2 RBD at a resolution of 3 Å, revealing similar binding mode as hACE2 to the SARS-CoV-2 RBD. These results shed light on pursuing the intermediate host of SARS-CoV-2 and highlight the necessity of monitoring susceptible hosts to prevent further outbreaks.

SELECTION OF CITATIONS
SEARCH DETAIL