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; Aguirre, Sara Cristina Cerf; Burger, Judith A.; Bouhuijs, Joey H.; Gibson, Grace; Schieffelin, John S.; Antanasijevic, Aleksandar; Boons, Geert‐Jan; Strecker, Thomas; Crispin, Max; Sanders, Rogier W.; Briney, Bryan; Ward, Andrew B.

doi:10.1016/j.celrep.2023.112524

Cited by 9 publications

(16 citation statements)

References 99 publications

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“…However, within the the head of GPC there are regions of high constraint, including, the core binding pocket for the primary host receptor, ɑ -DG. However, the putative binding region 78,79 to the secondary LAMP1 receptor is more mutationally tolerant, consistent with LAMP1 not being essential for infection 79,90–92 and different Lassa lineages have varying dependencies on LAMP1 for cell entry. 84…”

Section: Discussionmentioning

confidence: 62%

“…For instance, antibody 12.1F relies on five N-linked glycans (N89, N109, N119, N167, and N224) for binding to GPC, and mutations to the glycosylation motif sites tend to escape 12.1F (Figure S7C). 31,78 Similarly, antibody 8.9F relies on the N-linked glycan N119 (which is also important for GPC attachment to ɑ -DG) and mutations to this glycosylation site escape 8.9F (Figure S7C). 31 However, glycans do not explain all distal escape sites: for instance, antibody 12.1F is escaped by sites S135, I334, and N338, which cluster together buried below the surface of the GPC bound by the antibody (Figure S7D).…”

Section: Resultsmentioning

confidence: 99%

“…B Surface representation of Fab-bound GPC colored by site escape as measured in deep mutational scanning, with the Fab shown in a colored cartoon representation. Antibody 12.1F inhibits receptor binding and relies on five N-linked glycans (N89, N109, N119, N167, and N224) to bind to a single monomer of GPC 31,78 ; therefore, mutations to glycosylation motifs (N-X-S/T, X≠P) and to receptor binding sites escape antibody 12.1F neutralization as shown in C . Similarly, antibody 8.9F inhibits ɑ -DG binding and relies on the N-linked glycan N119 to bind across the three monomers of GPC 31 ; therefore, mutations to ɑ -DG binding sites and to the N119 glycosylation motif escape 8.9F neutralization as shown in C .…”

Section: Figure S1mentioning

confidence: 99%

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Deep mutational scanning reveals functional constraints and antigenic variability of Lassa virus glycoprotein complex

Carr,

Crawford,

Murphy

et al. 2024

Preprint

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Lassa virus is estimated to cause thousands of human deaths per year, primarily due to spillovers from its natural host,Mastomysrodents. Efforts to create vaccines and antibody therapeutics must account for the evolutionary variability of Lassa virus’s glycoprotein complex (GPC), which mediates viral entry into cells and is the target of neutralizing antibodies. To map the evolutionary space accessible to GPC, we use pseudovirus deep mutational scanning to measure how nearly all GPC amino-acid mutations affect cell entry and antibody neutralization. Our experiments define functional constraints throughout GPC. We quantify how GPC mutations affect neutralization by a panel of monoclonal antibodies and show that all antibodies are escaped by mutations that exist among natural Lassa virus lineages. Overall, our work describes a biosafety-level-2 method to elucidate the mutational space accessible to GPC and shows how prospective characterization of antigenic variation could aid design of therapeutics and vaccines.

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Section: Discussionmentioning

confidence: 62%

Section: Resultsmentioning

confidence: 99%

Section: Figure S1mentioning

confidence: 99%

See 1 more Smart Citation

Deep mutational scanning reveals functional constraints and antigenic variability of Lassa virus glycoprotein complex

Carr,

Crawford,

Murphy

et al. 2024

Preprint

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“…27,28 Since then, methods have been described to stabilize the trimeric conformation of prefusion GPC in the absence of a trimer-stabilizing mAb. 29–31 We previously demonstrated that prefusion GPC trimers are stabilized by genetic fusion to the trimeric scaffold I53-50A. 30,31 These fusion proteins, known as GPC-I53-50A, have not only proven to be a useful reagent for characterizing and isolating GPC-specific antibodies but also were able to induce NAb responses in rabbits.…”

Section: Introductionmentioning

confidence: 99%

“…30,31 These fusion proteins, known as GPC-I53-50A, have not only proven to be a useful reagent for characterizing and isolating GPC-specific antibodies but also were able to induce NAb responses in rabbits. 30,31…”

Section: Introductionmentioning

confidence: 99%

Defining bottlenecks and opportunities for Lassa virus neutralization by structural profiling of vaccine-induced polyclonal antibody responses

Brouwer,

Perrett,

Beaumont

et al. 2023

Preprint

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SummaryLassa fever continues to be a major public health burden in endemic countries in West Africa, yet effective therapies or vaccines are lacking. The isolation of potent and protective neutralizing antibodies against the Lassa virus glycoprotein complex (GPC) justifies the development of vaccines that can elicit strong neutralizing antibody responses. However, Lassa vaccines candidates have generally been unsuccessful in doing so and the associated antibody responses to these vaccines remain poorly characterized. Here, we establish an electron-microscopy based epitope mapping pipeline that enables high-resolution structural characterization of polyclonal antibodies to GPC. By applying this method to rabbits vaccinated with a recombinant GPC vaccine and a GPC-derived virus-like particle, we reveal determinants of neutralization which involve epitopes of the GPC-C, GPC-A, and GP1-A competition clusters. Furthermore, by identifying previously undescribed immunogenic off-target epitopes, we expose challenges that recombinant GPC vaccines face. By enabling detailed polyclonal antibody characterization, our work ushers in a next generation of more rational Lassa vaccine design.

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Rapid simulation of glycoprotein structures by grafting and steric exclusion of glycan conformer libraries

Tsai,

Chang,

Reuter

et al. 2024

Cell

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Structural conservation of Lassa virus glycoproteins and recognition by neutralizing antibodies

Cited by 9 publications

References 99 publications

Deep mutational scanning reveals functional constraints and antigenic variability of Lassa virus glycoprotein complex

Deep mutational scanning reveals functional constraints and antigenic variability of Lassa virus glycoprotein complex

Defining bottlenecks and opportunities for Lassa virus neutralization by structural profiling of vaccine-induced polyclonal antibody responses

Rapid simulation of glycoprotein structures by grafting and steric exclusion of glycan conformer libraries

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