Broad host range of SARS-CoV-2 predicted by comparative and structural analysis of ACE2 in vertebrates

There is no author summary for this article yet. Authors can add summaries to their articles on ScienceOpen to make them more accessible to a non-specialist audience.

Significance

The novel severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) is the cause of COVID-19, a major pandemic that threatens millions of human lives and the global economy. We identified a large number of mammals that can potentially be infected by SARS-CoV-2 via their ACE2 proteins. This can assist the identification of intermediate hosts for SARS-CoV-2 and hence reduce the opportunity for a future outbreak of COVID-19. Among the species we found with the highest risk for SARS-CoV-2 infection are wildlife and endangered species. These species represent an opportunity for spillover of SARS-CoV-2 from humans to other susceptible animals. Given the limited infectivity data for the species studied, we urge caution not to overinterpret the predictions of the present study.

Abstract

The novel coronavirus severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) is the cause of COVID-19. The main receptor of SARS-CoV-2, angiotensin I converting enzyme 2 (ACE2), is now undergoing extensive scrutiny to understand the routes of transmission and sensitivity in different species. Here, we utilized a unique dataset of ACE2 sequences from 410 vertebrate species, including 252 mammals, to study the conservation of ACE2 and its potential to be used as a receptor by SARS-CoV-2. We designed a five-category binding score based on the conservation properties of 25 amino acids important for the binding between ACE2 and the SARS-CoV-2 spike protein. Only mammals fell into the medium to very high categories and only catarrhine primates into the very high category, suggesting that they are at high risk for SARS-CoV-2 infection. We employed a protein structural analysis to qualitatively assess whether amino acid changes at variable residues would be likely to disrupt ACE2/SARS-CoV-2 spike protein binding and found the number of predicted unfavorable changes significantly correlated with the binding score. Extending this analysis to human population data, we found only rare (frequency <0.001) variants in 10/25 binding sites. In addition, we found significant signals of selection and accelerated evolution in the ACE2 coding sequence across all mammals, and specific to the bat lineage. Our results, if confirmed by additional experimental data, may lead to the identification of intermediate host species for SARS-CoV-2, guide the selection of animal models of COVID-19, and assist the conservation of animals both in native habitats and in human care.

Related collections

Most cited references 54

Record: found
Abstract: found
Article: found

Is Open Access

A pneumonia outbreak associated with a new coronavirus of probable bat origin

Peng Zhou, Xing-Lou Yang, Xian-Guang Wang … (2020)

Since the outbreak of severe acute respiratory syndrome (SARS) 18 years ago, a large number of SARS-related coronaviruses (SARSr-CoVs) have been discovered in their natural reservoir host, bats 1–4 . Previous studies have shown that some bat SARSr-CoVs have the potential to infect humans 5–7 . Here we report the identification and characterization of a new coronavirus (2019-nCoV), which caused an epidemic of acute respiratory syndrome in humans in Wuhan, China. The epidemic, which started on 12 December 2019, had caused 2,794 laboratory-confirmed infections including 80 deaths by 26 January 2020. Full-length genome sequences were obtained from five patients at an early stage of the outbreak. The sequences are almost identical and share 79.6% sequence identity to SARS-CoV. Furthermore, we show that 2019-nCoV is 96% identical at the whole-genome level to a bat coronavirus. Pairwise protein sequence analysis of seven conserved non-structural proteins domains show that this virus belongs to the species of SARSr-CoV. In addition, 2019-nCoV virus isolated from the bronchoalveolar lavage fluid of a critically ill patient could be neutralized by sera from several patients. Notably, we confirmed that 2019-nCoV uses the same cell entry receptor—angiotensin converting enzyme II (ACE2)—as SARS-CoV.

0 comments Cited 10102 times – based on 0 reviews      Review now

Bookmark

Record: found
Abstract: found
Article: not found

SARS-CoV-2 Cell Entry Depends on ACE2 and TMPRSS2 and Is Blocked by a Clinically Proven Protease Inhibitor

Markus Hoffmann, Hannah Kleine-Weber, Simon Schroeder … (2020)

Summary The recent emergence of the novel, pathogenic SARS-coronavirus 2 (SARS-CoV-2) in China and its rapid national and international spread pose a global health emergency. Cell entry of coronaviruses depends on binding of the viral spike (S) proteins to cellular receptors and on S protein priming by host cell proteases. Unravelling which cellular factors are used by SARS-CoV-2 for entry might provide insights into viral transmission and reveal therapeutic targets. Here, we demonstrate that SARS-CoV-2 uses the SARS-CoV receptor ACE2 for entry and the serine protease TMPRSS2 for S protein priming. A TMPRSS2 inhibitor approved for clinical use blocked entry and might constitute a treatment option. Finally, we show that the sera from convalescent SARS patients cross-neutralized SARS-2-S-driven entry. Our results reveal important commonalities between SARS-CoV-2 and SARS-CoV infection and identify a potential target for antiviral intervention.

0 comments Cited 9632 times – based on 0 reviews      Review now

Bookmark

Record: found
Abstract: found
Article: not found

Structure, Function, and Antigenicity of the SARS-CoV-2 Spike Glycoprotein

Alexandra C Walls, Young-Jun Park, M. Alejandra Tortorici … (2020)

Summary The emergence of SARS-CoV-2 has resulted in >90,000 infections and >3,000 deaths. Coronavirus spike (S) glycoproteins promote entry into cells and are the main target of antibodies. We show that SARS-CoV-2 S uses ACE2 to enter cells and that the receptor-binding domains of SARS-CoV-2 S and SARS-CoV S bind with similar affinities to human ACE2, correlating with the efficient spread of SARS-CoV-2 among humans. We found that the SARS-CoV-2 S glycoprotein harbors a furin cleavage site at the boundary between the S1/S2 subunits, which is processed during biogenesis and sets this virus apart from SARS-CoV and SARS-related CoVs. We determined cryo-EM structures of the SARS-CoV-2 S ectodomain trimer, providing a blueprint for the design of vaccines and inhibitors of viral entry. Finally, we demonstrate that SARS-CoV S murine polyclonal antibodies potently inhibited SARS-CoV-2 S mediated entry into cells, indicating that cross-neutralizing antibodies targeting conserved S epitopes can be elicited upon vaccination.

0 comments Cited 4093 times – based on 0 reviews      Review now

Bookmark

All references

Author and article information

Journal

Journal ID (nlm-ta): Proc Natl Acad Sci U S A

Journal ID (iso-abbrev): Proc. Natl. Acad. Sci. U.S.A

Journal ID (hwp): pnas

Journal ID (pmc): pnas

Journal ID (publisher-id): PNAS

Title: Proceedings of the National Academy of Sciences of the United States of America

Publisher: National Academy of Sciences

ISSN (Print): 0027-8424

ISSN (Electronic): 1091-6490

Publication date (Print): 8 September 2020

Publication date (Electronic): 21 August 2020

Publication date PMC-release: 21 August 2020

Volume: 117

Issue: 36

Pages: 22311-22322

Affiliations

[1] ^aThe Genome Center, University of California, Davis , CA 95616;

[2] ^bSchool of Biology and Environmental Science, University College Dublin , Belfield, Dublin 4, Ireland;

[3] ^cGraduate Program in Pharmaceutical Sciences and Pharmacogenomics, Quantitative Biosciences Consortium, University of California, San Francisco , CA 94117;

[4] ^dGladstone Institute of Data Science and Biotechnology , San Francisco, CA 94158;

[6] ^eCancer Program, Broad Institute of MIT and Harvard , Cambridge, MA 02142;

[7] ^fGenetic Perturbation Platform, Broad Institute of MIT and Harvard , Cambridge, MA 02142;

[8] ^gMax Planck Institute of Molecular Cell Biology and Genetics , 01307 Dresden, Germany;

[9] ^hMax Planck Institute for the Physics of Complex Systems , 01187 Dresden, Germany;

[10] ⁱCenter for Systems Biology Dresden , 01307 Dresden, Germany;

[11] ^jCenter for Species Survival, Smithsonian Conservation Biology Institute, National Zoological Park , Front Royal, VA 22630;

[12] ^kDepartment of Computational Biology, School of Computer Science, Carnegie Mellon University , Pittsburgh, PA 15213;

[13] ^lDepartment of Ecology, Tibetan Centre for Ecology and Conservation at WHU-TU, Hubei Key Laboratory of Cell Homeostasis, College of Life Sciences, Wuhan University , Wuhan 430072, China;

[14] ^mCollege of Science, Tibet University , Lhasa 850000, China;

[5] ⁿBroad Institute of MIT and Harvard, Cambridge, MA 02142;

[15] ^oDepartment of Epidemiology & Biostatistics, Institute for Computational Health Sciences, and Institute for Human Genetics, University of California, San Francisco, CA 94158;

[26] ^pChan Zuckerberg Biohub, San Francisco, CA 94158;

[16] ^qSan Diego Zoo Institute for Conservation Research , Escondido, CA 92027;

[17] ^rDepartment of Evolution, Behavior, and Ecology, Division of Biology, University of California San Diego , La Jolla, CA 92093;

[18] ^sDepartment of Restorative Dentistry and Biomaterials Sciences, Harvard School of Dental Medicine, Boston, MA 02115;

[19] ^tSchool of Dental Medicine, Case Western Reserve University , Cleveland, OH 44106;

[20] ^uMarine Mammal Program, Department of Vertebrate Zoology, Smithsonian Institution , Washington, DC 20002;

[21] ^vScience for Life Laboratory, Department of Medical Biochemistry and Microbiology, Uppsala University , 751 23 Uppsala, Sweden;

[22] ^wBioinformatics and Integrative Biology, University of Massachusetts Medical School , Worcester, MA 01655;

[23] ^xProgram in Molecular Medicine, University of Massachusetts Medical School , Worcester, MA 01655;

[24] ^yDepartment of Evolution and Ecology, University of California, Davis , CA 95616;

[25] ^zJohn Muir Institute for the Environment, University of California, Davis , CA 95616

Author notes

²To whom correspondence may be addressed. Email: Lewin@ 123456ucdavis.edu .

Edited by Scott V. Edwards, Harvard University, Cambridge, MA, and approved July 31, 2020 (received for review June 2, 2020)

Author contributions: J.D., C.A.P., E.C.T., E.K.K., and H.A.L. designed research; J.D., G.M.H., K.C.K., C.A.P., N.S.P., M.C., M.H., K.-P.K., H.Z., D.P.G., and R.S. performed research; J.D., G.M.H., K.C.K., C.A.P., N.S.P., M.C., M.H., K.-P.K., A.R.P., K.S.P., K.L.-T., E.C.T., E.K.K., and H.A.L. analyzed data; and J.D., G.M.H., K.C.K., C.A.P., N.S.P., M.C., M.H., K.-P.K., A.R.P., D.P.G., K.S.P., O.A.R., M.T.N., K.L.-T., E.C.T., E.K.K., and H.A.L. wrote the paper.

¹J.D., G.M.H., K.C.K., C.A.P., and N.S.P. contributed equally to this work.