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Foot-and-mouth disease virus antigenic landscape and reduced immunogenicity elucidated in atomic detail
Haozhou Li1, Pan Liu2,3, Hu Dong1
1State Key Laboratory for Animal Disease Control and Prevention, College of Veterinary Medicine, Lanzhou University, Lanzhou Veterinary Research Institute, Chinese Academy of Agricultural Sciences, Lanzhou, China.
Abstract:
Unlike most other picornaviruses, foot-and-mouth disease (FMD) intact virions (146S) dissociate easily into small pentameric subunits (12S). This causes a dramatically decreased immunogenicity by a mechanism that remains elusive. Here, we present the high-resolution structures of 12S (3.2 Å) and its immune complex of a single-domain antibody (VHH) targeting the particle interior (3.2 Å), as well as two 146S-specific VHHs complexed to distinct sites on the 146S capsid surface (3.6 Å and 2.9 Å). The antigenic landscape of 146S is depicted using 13 known FMD virus-antibody complexes. Comparison of the immunogenicity of 146S and 12S in pigs, focusing on the resulting antigenic sites and incorporating structural analysis, reveals that dissociation of 146S leads to structural alteration and destruction of multiple epitopes, resulting in significant differences in antibody profiles/lineages induced by 12S and 146S. Furthermore, 146S generates higher synergistic neutralizing antibody titers compared to 12S, whereas both particles induce similar total FMD virus specific antibody titers. This study can guide the structure-based rational design of novel multivalent and broad-spectrum recombinant vaccines for protection against FMD.
Insights
Foot-and-mouth disease virus (FMDV) intact virions (146S) dissociate into subunits (12S), altering epitopes and reducing immunogenicity. Understanding these structural changes guides the design of effective FMDV vaccines.
Area of Science:
- Virology
- Immunology
- Structural Biology
Background:
- Foot-and-mouth disease virus (FMDV) intact 146S virions readily dissociate into 12S subunits, a process linked to decreased immunogenicity.
- The precise mechanism by which FMDV dissociation impacts immunogenicity remains poorly understood.
Purpose of the Study:
- To elucidate the structural basis for the differential immunogenicity of FMDV 146S and 12S particles.
- To characterize the antigenic landscape of FMDV 146S and identify antibody binding sites.
Main Methods:
- High-resolution cryo-electron microscopy (cryo-EM) to determine structures of 12S, 146S, and their complexes with single-domain antibodies (VHHs).
- Analysis of 13 FMDV-antibody complexes to map the antigenic landscape.
- Comparative immunogenicity studies in pigs to assess antibody responses to 12S and 146S particles.
Main Results:
- Determined high-resolution structures of FMDV 12S and 146S particles complexed with VHH antibodies.
- Structural analysis revealed that FMDV 146S dissociation leads to epitope alteration and destruction.
- 146S particles induced higher synergistic neutralizing antibody titers compared to 12S particles, despite similar total antibody titers.
Conclusions:
- FMDV 146S dissociation significantly alters the antigenic surface, impacting antibody recognition and immune response.
- Structural insights into FMDV antigenicity can inform the rational design of improved recombinant vaccines.
- This work provides a foundation for developing multivalent and broad-spectrum FMDV vaccines.
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