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Cryo-EM structures of eastern equine encephalitis virus reveal mechanisms of virus disassembly and antibody neutralization

Cryo-EM structures of eastern equine encephalitis virus reveal mechanisms of virus disassembly and antibody neutralization
Cryo-EM structures of eastern equine encephalitis virus reveal mechanisms of virus disassembly and antibody neutralization

Alphaviruses are enveloped pathogens that cause arthritis and encephalitis. Here, we report a 4.4-Å cryoelectron microscopy (cryo-EM) structure of eastern equine encephalitis virus (EEEV), an alphavirus that causes fatal encephalitis in humans. Our analysis provides insights into viral entry into host cells. The envelope protein E2 showed a binding site for the cellular attachment factor heparan sulfate. The presence of a cryptic E2 glycan suggests how EEEV escapes surveillance by lectin-expressing myeloid lineage cells, which are sentinels of the immune system. A mechanism for nucleocapsid core release and disassembly upon viral entry was inferred based on pH changes and capsid dissociation from envelope proteins. The EEEV capsid structure showed a viral RNA genome binding site adjacent to a ribosome binding site for viral genome translation following genome release. Using five Fab-EEEV complexes derived from neutralizing antibodies, our investigation provides insights into EEEV host cell interactions and protective epitopes relevant to vaccine design. Hasan et al. use single-particle cryoelectron microscopy to elucidate the molecular basis of host cell entry of neurovirulent EEEV. They show that the EEEV envelope is primed for intracellular pH sensing and subsequent disassembly. Monoclonal antibodies effectively inhibit EEEV entry by cross-linking the viral envelope.

alphavirus, antibodies, conformational changes, cryoelectron microscopy, glycosylation, virus disassembly, virus entry
2211-1247
3136-3147.e5
Hasan, S. Saif
e7daad21-dc73-44e0-9790-b9258cb58472
Sun, Chengqun
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Kim, Arthur S.
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Watanabe, Yasunori
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Chen, Chun Liang
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Klose, Thomas
59955336-0fcd-4978-8325-011010ed6c89
Buda, Geeta
4178230d-4f03-4ae1-b05a-a80ac5e4a352
Crispin, Max
cd980957-0943-4b89-b2b2-710f01f33bc9
Diamond, Michael S.
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Klimstra, William B.
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Rossmann, Michael G.
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Hasan, S. Saif
e7daad21-dc73-44e0-9790-b9258cb58472
Sun, Chengqun
35ea6631-6bc2-4bf8-a398-83fb7f5b8b65
Kim, Arthur S.
905fce53-5cbf-4df2-b3ca-dc3848b0b984
Watanabe, Yasunori
8c0ee4af-a293-4de5-9036-3ce2051b380c
Chen, Chun Liang
226a83fb-3105-4a60-b7a1-7e62cba2817c
Klose, Thomas
59955336-0fcd-4978-8325-011010ed6c89
Buda, Geeta
4178230d-4f03-4ae1-b05a-a80ac5e4a352
Crispin, Max
cd980957-0943-4b89-b2b2-710f01f33bc9
Diamond, Michael S.
6895665c-3365-4c50-b26f-1471b5710509
Klimstra, William B.
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Rossmann, Michael G.
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Hasan, S. Saif, Sun, Chengqun, Kim, Arthur S., Watanabe, Yasunori, Chen, Chun Liang, Klose, Thomas, Buda, Geeta, Crispin, Max, Diamond, Michael S., Klimstra, William B. and Rossmann, Michael G. (2018) Cryo-EM structures of eastern equine encephalitis virus reveal mechanisms of virus disassembly and antibody neutralization. Cell Reports, 25 (11), 3136-3147.e5. (doi:10.1016/j.celrep.2018.11.067).

Record type: Article

Abstract

Alphaviruses are enveloped pathogens that cause arthritis and encephalitis. Here, we report a 4.4-Å cryoelectron microscopy (cryo-EM) structure of eastern equine encephalitis virus (EEEV), an alphavirus that causes fatal encephalitis in humans. Our analysis provides insights into viral entry into host cells. The envelope protein E2 showed a binding site for the cellular attachment factor heparan sulfate. The presence of a cryptic E2 glycan suggests how EEEV escapes surveillance by lectin-expressing myeloid lineage cells, which are sentinels of the immune system. A mechanism for nucleocapsid core release and disassembly upon viral entry was inferred based on pH changes and capsid dissociation from envelope proteins. The EEEV capsid structure showed a viral RNA genome binding site adjacent to a ribosome binding site for viral genome translation following genome release. Using five Fab-EEEV complexes derived from neutralizing antibodies, our investigation provides insights into EEEV host cell interactions and protective epitopes relevant to vaccine design. Hasan et al. use single-particle cryoelectron microscopy to elucidate the molecular basis of host cell entry of neurovirulent EEEV. They show that the EEEV envelope is primed for intracellular pH sensing and subsequent disassembly. Monoclonal antibodies effectively inhibit EEEV entry by cross-linking the viral envelope.

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Accepted/In Press date: 15 November 2018
e-pub ahead of print date: 11 December 2018
Published date: 11 December 2018
Keywords: alphavirus, antibodies, conformational changes, cryoelectron microscopy, glycosylation, virus disassembly, virus entry

Identifiers

Local EPrints ID: 426933
URI: http://eprints.soton.ac.uk/id/eprint/426933
ISSN: 2211-1247
PURE UUID: e8ca428d-c514-448e-be33-e6807616a422
ORCID for Max Crispin: ORCID iD orcid.org/0000-0002-1072-2694

Catalogue record

Date deposited: 18 Dec 2018 17:30
Last modified: 26 Nov 2021 03:11

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Contributors

Author: S. Saif Hasan
Author: Chengqun Sun
Author: Arthur S. Kim
Author: Yasunori Watanabe
Author: Chun Liang Chen
Author: Thomas Klose
Author: Geeta Buda
Author: Max Crispin ORCID iD
Author: Michael S. Diamond
Author: William B. Klimstra
Author: Michael G. Rossmann

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