Enhancing foot-and-mouth disease virus thermostability with a VP1 substitution selected by host HSP60 inhibition.
- 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, 730000, People's Republic of China.
- 2Gembloux Agro-Biotech, University of Liege, Gembloux, Belgium.
- 3State Key Laboratory for Animal Disease Control and Prevention, College of Veterinary Medicine, Lanzhou University, Lanzhou Veterinary Research Institute, Chinese Academy of Agricultural Sciences, Lanzhou, 730000, People's Republic of China. [email protected].
Abstract
Foot-and-mouth disease virus (FMDV) exhibits greater temperature sensitivity compared to many other picornaviruses, which poses a substantial challenge for the stability of inactivated vaccines. Therefore, enhancing the thermal stability of the FMDV capsid is crucial. FMDV exists as a quasispecies with high mutation rates, providing a basis for selection under pressure. Our group previously discovered that heat shock protein HSP60 was recruited to support FMDV replication by promoting the assembly of the viral replication complex (RC). By applying the HSP60 inhibitor mizoribine, we selected FMDV variants with enhanced fitness under conditions of impaired HSP60 function. Subsequent sequencing of the selected populations and reverse genetics approaches identified a key amino acid substitution, T171P in the viral VP1 protein that confers resistance to the HSP60 inhibitor. Structural simulation predicted that the T171P substitution enhances the stability of the VP1 protein, which was further supported by experimental evidence demonstrating increased thermal stability of the whole viral capsid. A series of experiments, including virion stability assessment using the PaSTRy assay, quantification of intact particles following heat challenge, and evaluation of viral infectivity at elevated temperatures, demonstrated that the T171P-VP1 variant possesses enhanced thermostability compared to the wild-type (WT) virus. Furthermore, immunization experiments showed that the inactivated T171P-VP1 variant, after heat challenge, elicited a stronger neutralizing antibody response than the similarly treated WT virus. This study identifies a novel amino acid substitution that significantly enhances FMDV thermostability. This finding not only provides a viable strategy for improving the thermal stability of FMD vaccines but also opens new avenues for exploring the intricate mechanisms of host-virus interaction. KEY POINTS: • A novel HSP60 inhibitor-based selection strategy identified the T171P-VP1 substitution conferring enhanced viral fitness. • The T171P substitution significantly improves FMDV capsid thermostability compared to the wild-type virus. • The inactivated T171P-VP1 variant induces stronger neutralizing antibody responses after heat challenge, offering a promising approach for thermostable FMD vaccine development.
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BibTeX
@article{ren2026enhancing,
title = {{Enhancing foot-and-mouth disease virus thermostability with a VP1 substitution selected by host HSP60 inhibition.}},
author = {Mei Ren and Haiqian Zhou and Hu Dong and Jinen Wu and Jianing Wang and Jiaxi Yu and Huichen Guo and Shiqi Sun},
journal = {Applied microbiology and biotechnology},
year = {2026},
month = jul,
doi = {10.1007/s00253-026-13971-2},
url = {https://europepmc.org/article/MED/42909628},
note = {CC BY-NC-ND},
}
RIS
TY - JOUR
TI - Enhancing foot-and-mouth disease virus thermostability with a VP1 substitution selected by host HSP60 inhibition.
AU - Mei Ren
AU - Haiqian Zhou
AU - Hu Dong
AU - Jinen Wu
AU - Jianing Wang
AU - Jiaxi Yu
AU - Huichen Guo
AU - Shiqi Sun
PY - 2026
DA - 2026/07/01
JO - Applied microbiology and biotechnology
DO - 10.1007/s00253-026-13971-2
UR - https://europepmc.org/article/MED/42909628
AB - Foot-and-mouth disease virus (FMDV) exhibits greater temperature sensitivity compared to many other picornaviruses, which poses a substantial challenge for the stability of inactivated vaccines. Therefore, enhancing the thermal stability of the FMDV capsid is crucial. FMDV exists as a quasispecies with high mutation rates, providing a basis for selection under pressure. Our group previously discovered that heat shock protein HSP60 was recruited to support FMDV replication by promoting the assembly of the viral replication complex (RC). By applying the HSP60 inhibitor mizoribine, we selected FMDV variants with enhanced fitness under conditions of impaired HSP60 function. Subsequent sequencing of the selected populations and reverse genetics approaches identified a key amino acid substitution, T171P in the viral VP1 protein that confers resistance to the HSP60 inhibitor. Structural simulation predicted that the T171P substitution enhances the stability of the VP1 protein, which was further supported by experimental evidence demonstrating increased thermal stability of the whole viral capsid. A series of experiments, including virion stability assessment using the PaSTRy assay, quantification of intact particles following heat challenge, and evaluation of viral infectivity at elevated temperatures, demonstrated that the T171P-VP1 variant possesses enhanced thermostability compared to the wild-type (WT) virus. Furthermore, immunization experiments showed that the inactivated T171P-VP1 variant, after heat challenge, elicited a stronger neutralizing antibody response than the similarly treated WT virus. This study identifies a novel amino acid substitution that significantly enhances FMDV thermostability. This finding not only provides a viable strategy for improving the thermal stability of FMD vaccines but also opens new avenues for exploring the intricate mechanisms of host-virus interaction. KEY POINTS: • A novel HSP60 inhibitor-based selection strategy identified the T171P-VP1 substitution conferring enhanced viral fitness. • The T171P substitution significantly improves FMDV capsid thermostability compared to the wild-type virus. • The inactivated T171P-VP1 variant induces stronger neutralizing antibody responses after heat challenge, offering a promising approach for thermostable FMD vaccine development.
SN - 0175-7598
SN - 1432-0614
ER -