Structural conservation of Lassa virus glycoproteins and recognition by neutralizing antibodies
Structural conservation of Lassa virus glycoproteins and recognition by neutralizing antibodies
Lassa fever is an acute hemorrhagic fever caused by the zoonotic Lassa virus (LASV). The LASV glycoprotein complex (GPC) mediates viral entry and is the sole target for neutralizing antibodies. Immunogen design is complicated by the metastable nature of recombinant GPCs and the antigenic differences among phylogenetically distinct LASV lineages. Despite the sequence diversity of the GPC, structures of most lineages are lacking. We present the development and characterization of prefusion-stabilized, trimeric GPCs of LASV lineages II, V, and VII, revealing structural conservation despite sequence diversity. High-resolution structures and biophysical characterization of the GPC in complex with GP1-A-specific antibodies suggest their neutralization mechanisms. Finally, we present the isolation and characterization of a trimer-preferring neutralizing antibody belonging to the GPC-B competition group with an epitope that spans adjacent protomers and includes the fusion peptide. Our work provides molecular detail information on LASV antigenic diversity and will guide efforts to design pan-LASV vaccines.
Perrett, Hailee R.
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Brouwer, Philip J.M.
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Hurtado, Jonathan
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Newby, Maddy L.
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Liu, Lin
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Müller-Kräuter, Helena
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Müller Aguirre, Sarah
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Burger, Judith A.
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Bouhuijs, Joey H.
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Gibson, Grace
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Messmer, Terrence
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Schieffelin, John S
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Antanasijevic, Aleksandar
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Boons, Geert-Jan
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Strecker, Thomas
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Crispin, Max
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Sanders, Rogier W.
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Briney, Bryan
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Ward, Andrew B.
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30 May 2023
Perrett, Hailee R.
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Brouwer, Philip J.M.
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Hurtado, Jonathan
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Newby, Maddy L.
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Liu, Lin
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Müller-Kräuter, Helena
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Müller Aguirre, Sarah
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Burger, Judith A.
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Bouhuijs, Joey H.
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Gibson, Grace
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Messmer, Terrence
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Schieffelin, John S
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Antanasijevic, Aleksandar
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Boons, Geert-Jan
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Strecker, Thomas
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Crispin, Max
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Sanders, Rogier W.
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Briney, Bryan
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Ward, Andrew B.
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Perrett, Hailee R., Brouwer, Philip J.M., Hurtado, Jonathan, Newby, Maddy L., Liu, Lin, Müller-Kräuter, Helena, Müller Aguirre, Sarah, Burger, Judith A., Bouhuijs, Joey H., Gibson, Grace, Messmer, Terrence, Schieffelin, John S, Antanasijevic, Aleksandar, Boons, Geert-Jan, Strecker, Thomas, Crispin, Max, Sanders, Rogier W., Briney, Bryan and Ward, Andrew B.
(2023)
Structural conservation of Lassa virus glycoproteins and recognition by neutralizing antibodies.
Cell Reports, 42 (5), [112524].
(doi:10.1016/j.celrep.2023.112524).
Abstract
Lassa fever is an acute hemorrhagic fever caused by the zoonotic Lassa virus (LASV). The LASV glycoprotein complex (GPC) mediates viral entry and is the sole target for neutralizing antibodies. Immunogen design is complicated by the metastable nature of recombinant GPCs and the antigenic differences among phylogenetically distinct LASV lineages. Despite the sequence diversity of the GPC, structures of most lineages are lacking. We present the development and characterization of prefusion-stabilized, trimeric GPCs of LASV lineages II, V, and VII, revealing structural conservation despite sequence diversity. High-resolution structures and biophysical characterization of the GPC in complex with GP1-A-specific antibodies suggest their neutralization mechanisms. Finally, we present the isolation and characterization of a trimer-preferring neutralizing antibody belonging to the GPC-B competition group with an epitope that spans adjacent protomers and includes the fusion peptide. Our work provides molecular detail information on LASV antigenic diversity and will guide efforts to design pan-LASV vaccines.
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Accepted/In Press date: 1 May 2023
e-pub ahead of print date: 18 May 2023
Published date: 30 May 2023
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Local EPrints ID: 477803
URI: http://eprints.soton.ac.uk/id/eprint/477803
ISSN: 2211-1247
PURE UUID: 9451619d-3419-43cf-8009-f99fc46952d2
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Date deposited: 14 Jun 2023 16:52
Last modified: 16 Apr 2024 01:51
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Contributors
Author:
Hailee R. Perrett
Author:
Philip J.M. Brouwer
Author:
Jonathan Hurtado
Author:
Maddy L. Newby
Author:
Lin Liu
Author:
Helena Müller-Kräuter
Author:
Sarah Müller Aguirre
Author:
Judith A. Burger
Author:
Joey H. Bouhuijs
Author:
Grace Gibson
Author:
Terrence Messmer
Author:
John S Schieffelin
Author:
Aleksandar Antanasijevic
Author:
Geert-Jan Boons
Author:
Thomas Strecker
Author:
Rogier W. Sanders
Author:
Bryan Briney
Author:
Andrew B. Ward
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