Structural conservation of Lassa virus glycoproteins and recognition by neutralizing antibodies
Hailee R. Perrett,
Philip J.M. Brouwer,
Jonathan Hurtado,
Maddy L. Newby,
Lin Liu,
Helena Müller-Kräuter,
Sarah Müller 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
Hailee R. Perrett
Department of Integrative, Structural and Computational Biology, The Scripps Research Institute, La Jolla, CA 92037, USA
Philip J.M. Brouwer
Department of Integrative, Structural and Computational Biology, The Scripps Research Institute, La Jolla, CA 92037, USA
Jonathan Hurtado
Department of Immunology and Microbiology, Scripps Research, La Jolla, CA 92037, USA; Center for Viral Systems Biology, Scripps Research, La Jolla, CA 92037, USA
Maddy L. Newby
School of Biological Sciences, University of Southampton, Southampton SO17 1BJ, UK
Lin Liu
Complex Carbohydrate Research Center, University of Georgia, Athens, GA 30602, USA
Helena Müller-Kräuter
Institute of Virology, Philipps University Marburg, 35043 Marburg, Germany
Sarah Müller Aguirre
Institute of Virology, Philipps University Marburg, 35043 Marburg, Germany
Judith A. Burger
Department of Medical Microbiology and Infection Prevention, Amsterdam University Medical Centers. Location AMC, University of Amsterdam, Amsterdam Infection & Immunity Institute, Amsterdam 1105 AZ, the Netherlands
Joey H. Bouhuijs
Department of Medical Microbiology and Infection Prevention, Amsterdam University Medical Centers. Location AMC, University of Amsterdam, Amsterdam Infection & Immunity Institute, Amsterdam 1105 AZ, the Netherlands
Grace Gibson
Department of Integrative, Structural and Computational Biology, The Scripps Research Institute, La Jolla, CA 92037, USA
Terrence Messmer
Department of Immunology and Microbiology, Scripps Research, La Jolla, CA 92037, USA
John S. Schieffelin
Department of Pediatrics, Tulane University School of Medicine, New Orleans, LA 70112, USA
Aleksandar Antanasijevic
Department of Integrative, Structural and Computational Biology, The Scripps Research Institute, La Jolla, CA 92037, USA
Geert-Jan Boons
Complex Carbohydrate Research Center, University of Georgia, Athens, GA 30602, USA; Department of Chemical Biology and Drug Discovery, Utrecht University, Utrecht 3584 CG, the Netherlands
Thomas Strecker
Institute of Virology, Philipps University Marburg, 35043 Marburg, Germany
Max Crispin
School of Biological Sciences, University of Southampton, Southampton SO17 1BJ, UK
Rogier W. Sanders
Department of Medical Microbiology and Infection Prevention, Amsterdam University Medical Centers. Location AMC, University of Amsterdam, Amsterdam Infection & Immunity Institute, Amsterdam 1105 AZ, the Netherlands; Department of Microbiology and Immunology, Weill Medical College of Cornell University, New York, NY 10021, USA
Bryan Briney
Department of Immunology and Microbiology, Scripps Research, La Jolla, CA 92037, USA; Center for Viral Systems Biology, Scripps Research, La Jolla, CA 92037, USA
Andrew B. Ward
Department of Integrative, Structural and Computational Biology, The Scripps Research Institute, La Jolla, CA 92037, USA; Corresponding author
Summary: 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.
