Department of Integrative, Structural and Computational Biology, The Scripps Research Institute, La Jolla, CA 92037, USA.
Department of Immunology and Microbiology, Scripps Research, La Jolla, CA 92037, USA; Center for Viral Systems Biology, Scripps Research, La Jolla, CA 92037, USA.
Cell Rep. 2023 May 30;42(5):112524. doi: 10.1016/j.celrep.2023.112524. Epub 2023 May 18.
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.
拉沙热是一种由人畜共患的拉沙病毒（LASV）引起的急性出血热。LASV 糖蛋白复合物（GPC）介导病毒进入，是唯一针对中和抗体的靶标。免疫原设计受到重组 GPC 的亚稳态性质和系统发育上不同 LASV 谱系之间的抗原差异的影响。尽管 GPC 存在序列多样性，但大多数谱系的结构仍不清楚。我们介绍了 LASV 谱系 II、V 和 VII 的预融合稳定三聚体 GPC 的开发和表征，尽管存在序列多样性，但仍显示出结构保守性。与 GP1-A 特异性抗体结合的 GPC 的高分辨率结构和生物物理特性表明了它们的中和机制。最后，我们介绍了一种属于 GPC-B 竞争组的三聚体偏好中和抗体的分离和表征，该抗体的表位跨越相邻的原聚体，并包含融合肽。我们的工作提供了关于 LASV 抗原多样性的分子细节信息，并将指导设计泛 LASV 疫苗的努力。
