Structural Conservation of Lassa Virus Glycoproteins and Recognition by Neutralizing Antibodies

Overview

Journal Cell Rep

Publisher Cell Press

Specialties Biology
Cell Biology
Molecular Biology

Date 2023 May 20

PMID 37209096

Authors

Hailee R Perrett

Philip J M Brouwer

Jonathan Hurtado

Maddy L Newby

Lin Liu

Helena Muller-Krauter

Sarah Muller Aguirre

Judith A Burger

Joey H Bouhuijs

Grace Gibson

Terrence Messmer

John S Schieffelin

Aleksandar Antanasijevic

Geert-Jan Boons

Thomas Strecker

Max Crispin

Rogier W Sanders

Bryan Briney

Andrew B Ward

Affiliations

Soon will be listed here.

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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References

Zhang Y, de la Torre J, Melikyan G . Human LAMP1 accelerates Lassa virus fusion and potently promotes fusion pore dilation upon forcing viral fusion with non-endosomal membrane. PLoS Pathog. 2022; 18(8):e1010625. PMC: 9410554. DOI: 10.1371/journal.ppat.1010625. View

Li Y, Tian H . Adaptive genetic diversification of Lassa virus associated with the epidemic split of north-central Nigerian and non-Nigerian lineages. Virology. 2020; 545:10-15. DOI: 10.1016/j.virol.2020.03.002. View

Brouwer P, Antanasijevic A, Ronk A, Muller-Krauter H, Watanabe Y, Claireaux M . Lassa virus glycoprotein nanoparticles elicit neutralizing antibody responses and protection. Cell Host Microbe. 2022; 30(12):1759-1772.e12. PMC: 9794196. DOI: 10.1016/j.chom.2022.10.018. View

Siddle K, Eromon P, Barnes K, Mehta S, Oguzie J, Odia I . Genomic Analysis of Lassa Virus during an Increase in Cases in Nigeria in 2018. N Engl J Med. 2018; 379(18):1745-1753. PMC: 6181183. DOI: 10.1056/NEJMoa1804498. View

Katz M, Weinstein J, Eilon-Ashkenazy M, Gehring K, Cohen-Dvashi H, Elad N . Structure and receptor recognition by the Lassa virus spike complex. Nature. 2022; 603(7899):174-179. DOI: 10.1038/s41586-022-04429-2. View

Goncalves A, Moraz M, Pasquato A, Helenius A, Lozach P, Kunz S . Role of DC-SIGN in Lassa virus entry into human dendritic cells. J Virol. 2013; 87(21):11504-15. PMC: 3807329. DOI: 10.1128/JVI.01893-13. View

Robinson J, Hastie K, Cross R, Yenni R, Elliott D, Rouelle J . Most neutralizing human monoclonal antibodies target novel epitopes requiring both Lassa virus glycoprotein subunits. Nat Commun. 2016; 7:11544. PMC: 4866400. DOI: 10.1038/ncomms11544. View

Leem J, Dunbar J, Georges G, Shi J, Deane C . ABodyBuilder: Automated antibody structure prediction with data-driven accuracy estimation. MAbs. 2016; 8(7):1259-1268. PMC: 5058620. DOI: 10.1080/19420862.2016.1205773. View

Pickett B, Sadat E, Zhang Y, Noronha J, Squires R, Hunt V . ViPR: an open bioinformatics database and analysis resource for virology research. Nucleic Acids Res. 2011; 40(Database issue):D593-8. PMC: 3245011. DOI: 10.1093/nar/gkr859. View

10.

Re S, Mizuguchi K . Glycan Cluster Shielding and Antibody Epitopes on Lassa Virus Envelop Protein. J Phys Chem B. 2021; 125(8):2089-2097. DOI: 10.1021/acs.jpcb.0c11516. View

11.

Mehand M, Al-Shorbaji F, Millett P, Murgue B . The WHO R&D Blueprint: 2018 review of emerging infectious diseases requiring urgent research and development efforts. Antiviral Res. 2018; 159:63-67. PMC: 7113760. DOI: 10.1016/j.antiviral.2018.09.009. View

12.

Sommerstein R, Flatz L, Remy M, Malinge P, Magistrelli G, Fischer N . Arenavirus Glycan Shield Promotes Neutralizing Antibody Evasion and Protracted Infection. PLoS Pathog. 2015; 11(11):e1005276. PMC: 4654586. DOI: 10.1371/journal.ppat.1005276. View

13.

Akpede G, Asogun D, Okogbenin S, Dawodu S, Momoh M, Dongo A . Caseload and Case Fatality of Lassa Fever in Nigeria, 2001-2018: A Specialist Center's Experience and Its Implications. Front Public Health. 2019; 7:170. PMC: 6603170. DOI: 10.3389/fpubh.2019.00170. View

14.

Markosyan R, Marin M, Zhang Y, Cohen F, Melikyan G . The late endosome-resident lipid bis(monoacylglycero)phosphate is a cofactor for Lassa virus fusion. PLoS Pathog. 2021; 17(9):e1009488. PMC: 8448326. DOI: 10.1371/journal.ppat.1009488. View

15.

Cohen-Dvashi H, Israeli H, Shani O, Katz A, Diskin R . Role of LAMP1 Binding and pH Sensing by the Spike Complex of Lassa Virus. J Virol. 2016; 90(22):10329-10338. PMC: 5105667. DOI: 10.1128/JVI.01624-16. View

16.

Emsley P, Crispin M . Structural analysis of glycoproteins: building N-linked glycans with Coot. Acta Crystallogr D Struct Biol. 2018; 74(Pt 4):256-263. PMC: 5892875. DOI: 10.1107/S2059798318005119. View

17.

Lander G, Stagg S, Voss N, Cheng A, Fellmann D, Pulokas J . Appion: an integrated, database-driven pipeline to facilitate EM image processing. J Struct Biol. 2009; 166(1):95-102. PMC: 2775544. DOI: 10.1016/j.jsb.2009.01.002. View

18.

Agirre J, Iglesias-Fernandez J, Rovira C, Davies G, Wilson K, Cowtan K . Privateer: software for the conformational validation of carbohydrate structures. Nat Struct Mol Biol. 2015; 22(11):833-4. DOI: 10.1038/nsmb.3115. View

19.

Pettersen E, Goddard T, Huang C, Couch G, Greenblatt D, Meng E . UCSF Chimera--a visualization system for exploratory research and analysis. J Comput Chem. 2004; 25(13):1605-12. DOI: 10.1002/jcc.20084. View

20.

Thielebein A, Ighodalo Y, Taju A, Olokor T, Omiunu R, Esumeh R . Virus persistence after recovery from acute Lassa fever in Nigeria: a 2-year interim analysis of a prospective longitudinal cohort study. Lancet Microbe. 2022; 3(1):e32-e40. DOI: 10.1016/S2666-5247(21)00178-6. View