Structural conservation of Lassa virus glycoproteins and recognition by neutralizing antibodies
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; Ward, Andrew B.
(2023) Cell Reports, volume 42, issue 5, pp. 1 - 27
(Article)
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.
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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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Keywords: arenavirus, CP: Immunology, cryo-EM, Lassa fever, Lassa mammarenavirus, neutralizing antibody, prefusion glycoprotein, structure-based vaccine design, General Biochemistry,Genetics and Molecular Biology
ISSN: 2211-1247
Publisher: Elsevier Saunders
Note: Funding Information: The authors thank Bill Anderson and Hannah Turner from The Scripps Research Institute for their help with EM experiments. We thank Lauren Holden and Gabriel Ozorowski for their help in preparing this article. We also thank Thijn Brummelkamp, Lars Hangartner, and Robin Shattock for kindly sharing the LAMP-1, BirA, and full-length and native Josiah GPC plasmids, respectively. We kindly thank Robert F. Garry for help with sample acquisition and collection from the Lassa fever survivor cohort at the Kenema Government Hospital. We also thank Gotthard Ludwig and Sebastian Schmidt from the biosafety level 4 facility at the Philipps-University of Marburg for technical assistance. H.R.P. is supported by a David C. Fairchild Endowed Fellowship , Achievement Rewards for College Scientists Foundation, and NIH F31 Ruth L. Kirschstein Predoctoral Award 1F31Al172358 . P.J.M.B. is supported by a Rubicon fellowship from the Netherlands Organisation for Scientific Research (NWO). A.A. is supported by the amfAR Mathilde Krim Fellowship in Biomedical Research ( #110182-69-RKVA ). Further support from the Vici fellowship from the Netherlands Organisation for Scientific Research (NWO; to R.W.S.); by the Fondation Dormeur , Vaduz (to R.W.S.); by NIH grant R01 AI165692 (to G.-J.B.); by the Deutsche Forschungsgemeinschaft (DFG, German Research Foundation)-Projektnummer 197785619/SFB1021 (to T.S.); by the International AIDS Vaccine Initiative (IAVI) through grant INV-008352/OPP1153692 funded by the Bill and Melinda Gates Foundation (to M.C.); by NIH grant R01 AI171438 (to B.B. and A.B.W.); and by the Bill and Melinda Gates Foundation through grant OPP1170236 (to A.B.W.) enabled this work. Funding Information: The authors thank Bill Anderson and Hannah Turner from The Scripps Research Institute for their help with EM experiments. We thank Lauren Holden and Gabriel Ozorowski for their help in preparing this article. We also thank Thijn Brummelkamp, Lars Hangartner, and Robin Shattock for kindly sharing the LAMP-1, BirA, and full-length and native Josiah GPC plasmids, respectively. We kindly thank Robert F. Garry for help with sample acquisition and collection from the Lassa fever survivor cohort at the Kenema Government Hospital. We also thank Gotthard Ludwig and Sebastian Schmidt from the biosafety level 4 facility at the Philipps-University of Marburg for technical assistance. H.R.P. is supported by a David C. Fairchild Endowed Fellowship, Achievement Rewards for College Scientists Foundation, and NIH F31 Ruth L. Kirschstein Predoctoral Award 1F31Al172358. P.J.M.B. is supported by a Rubicon fellowship from the Netherlands Organisation for Scientific Research (NWO). A.A. is supported by the amfAR Mathilde Krim Fellowship in Biomedical Research (#110182-69-RKVA). Further support from the Vici fellowship from the Netherlands Organisation for Scientific Research (NWO; to R.W.S.); by the Fondation Dormeur, Vaduz (to R.W.S.); by NIH grant R01 AI165692 (to G.-J.B.); by the Deutsche Forschungsgemeinschaft (DFG, German Research Foundation)-Projektnummer 197785619/SFB1021 (to T.S.); by the International AIDS Vaccine Initiative (IAVI) through grant INV-008352/OPP1153692 funded by the Bill and Melinda Gates Foundation (to M.C.); by NIH grant R01 AI171438 (to B.B. and A.B.W.); and by the Bill and Melinda Gates Foundation through grant OPP1170236 (to A.B.W.) enabled this work. Conceptualization, H.R.P. P.J.M.B. A.A. and A.B.W.; methodology, H.R.P. P.J.M.B. J.H. M.L.N. L.L. J.A.B. B.B. S.M.A. and H.M.-K.; formal analysis, H.R.P. P.J.M.B. J.H. M.L.N. and A.A.; investigation, H.R.P. P.J.M.B. J.H. M.L.N. L.L. S.M.A. H.M.-K. J.A.B. J.H.B. G.G. T.M. and B.B.; resources, J.S.S. G.-J.B. T.S. M.C. R.W.S. B.B. and A.B.W.; writing – original draft, H.R.P. P.J.M.B. and A.B.W.; reviewing, editing, and other feedback, H.R.P. P.J.M.B. J.H. M.L.N. L.L. S.M.A. H.M.-K. J.A.B. J.H.B. G.G. T.M. J.S.S. A.A. G.-J.B. T.S. M.C. R.W.S. B.B. and A.B.W.; visualization, H.R.P. M.L.N. L.L. S.M.A. H.M.-K. J.A.B. and J.H.B.; supervision, A.A. G.-J.B. T.S. M.C. R.W.S. B.B. and A.B.W.; project administration, H.R.P. P.J.M.B. and A.B.W.; funding acquisition, H.R.P. P.J.M.B. G.-J.B. T.S. M.C. R.W.S. B.B. and A.B.W. The authors declare no competing interests. Publisher Copyright: © 2023 The Authors
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