Thermostability of the foot-and-mouth disease virus capsid is modulated by lethal and viability-restoring compensatory amino acid substitutions

Research output: Contribution to journalJournal articleResearchpeer-review

  • Silvia López-Argüello
  • Verónica Rincón
  • Alicia Rodríguez-Huete
  • Encarnación Martínez-Salas
  • Belsham, Graham John
  • Alejandro Valbuena
  • Mauricio G. Mateu

Infection by viruses depends on a balance between capsid stability and dynamics. This study investigated biologically and biotechnologically relevant aspects of the relationship in foot-and-mouth disease virus (FMDV) between capsid structure and thermostability and between thermostability and infectivity. In the FMDV capsid, a substantial number of amino acid side chains at the interfaces between pentameric subunits are charged at neutral pH. Here a mutational analysis revealed that the essential role for virus infection of most of the 8 tested charged groups is not related to substantial changes in capsid protein expression or processing or in capsid assembly or stability against a thermally induced dissociation into pentamers. However, the positively charged side chains of R2018 and H3141, located at the interpentamer interfaces close to the capsid 2-fold symmetry axes, were found to be critical both for virus infectivity and for keeping the capsid in a state of weak thermostability. A charge-restoring substitution (N2019H) that was repeatedly fixed during amplification of viral genomes carrying deleterious mutations reverted both the lethal and capsid-stabilizing effects of the substitution H3141A, leading to a double mutant virus with close to normal infectivity and thermolability. H3141A and other thermostabilizing substitutions had no detectable effect on capsid resistance to acid-induced dissociation into pentamers. The results suggest that FMDV infectivity requires limited local stability around the 2-fold axes at the interpentamer interfaces of the capsid. The implications for the mechanism of genome uncoating in FMDV and the development of thermostabilized vaccines against foot-and-mouth disease are discussed. IMPORTANCE This study provides novel insights into the little-known structural determinants of the balance between thermal stability and instability in the capsid of foot-and-mouth disease virus and into the relationship between capsid stability and virus infectivity. The results provide new guidelines for the development of thermostabilized empty capsid-based recombinant vaccines against foot-and-mouth disease, one of the economically most important animal diseases worldwide.

Original languageEnglish
Article numbere02293-18
JournalJournal of Virology
Issue number10
Publication statusPublished - 2019
Externally publishedYes

    Research areas

  • Capsid, Foot-and-mouth disease virus, Protein engineering, Thermal stability, Vaccine

ID: 238754606