Thermostability of the foot-and-mouth disease virus capsid is modulated by lethal and viability-restoring compensatory amino acid substitutions
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Thermostability of the foot-and-mouth disease virus capsid is modulated by lethal and viability-restoring compensatory amino acid substitutions. / López-Argüello, Silvia; Rincón, Verónica; Rodríguez-Huete, Alicia; Martínez-Salas, Encarnación; Belsham, Graham J.; Valbuena, Alejandro; Mateu, Mauricio G.
In: Journal of Virology, Vol. 93, No. 10, e02293-18, 2019.Research output: Contribution to journal › Journal article › Research › peer-review
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T1 - Thermostability of the foot-and-mouth disease virus capsid is modulated by lethal and viability-restoring compensatory amino acid substitutions
AU - López-Argüello, Silvia
AU - Rincón, Verónica
AU - Rodríguez-Huete, Alicia
AU - Martínez-Salas, Encarnación
AU - Belsham, Graham J.
AU - Valbuena, Alejandro
AU - Mateu, Mauricio G.
PY - 2019
Y1 - 2019
N2 - 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.
AB - 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.
KW - Capsid
KW - Foot-and-mouth disease virus
KW - Protein engineering
KW - Thermal stability
KW - Vaccine
U2 - 10.1128/JVI.02293-18
DO - 10.1128/JVI.02293-18
M3 - Journal article
C2 - 30867300
AN - SCOPUS:85065528422
VL - 93
JO - Journal of Virology
JF - Journal of Virology
SN - 0022-538X
IS - 10
M1 - e02293-18
ER -
ID: 238754606