Genetic Determinants of Virulence between Two Foot-and-Mouth Disease Virus Isolates Which Caused Outbreaks of Differing Severity

ABSTRACT Individual foot-and-mouth disease virus (FMDV) strains reveal different degrees of infectivity and pathogenicity in host animals. The differences in severity among outbreaks might be ascribable to these differences in infectivity among FMDV strains. To investigate the molecular mechanisms u...

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Autores principales:	Tatsuya Nishi, Kazuki Morioka, Nobuko Saito, Makoto Yamakawa, Toru Kanno, Katsuhiko Fukai
Formato:	article
Lenguaje:	EN
Publicado:	American Society for Microbiology 2019
Materias:	foot-and-mouth disease virus genetic determinants virulence Microbiology QR1-502
Acceso en línea:	https://doaj.org/article/de074b6356534f419d9bfc95923f03bf
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spelling	oai:doaj.org-article:de074b6356534f419d9bfc95923f03bf2021-11-15T15:22:26ZGenetic Determinants of Virulence between Two Foot-and-Mouth Disease Virus Isolates Which Caused Outbreaks of Differing Severity10.1128/mSphere.00294-192379-5042https://doaj.org/article/de074b6356534f419d9bfc95923f03bf2019-08-01T00:00:00Zhttps://journals.asm.org/doi/10.1128/mSphere.00294-19https://doaj.org/toc/2379-5042ABSTRACT Individual foot-and-mouth disease virus (FMDV) strains reveal different degrees of infectivity and pathogenicity in host animals. The differences in severity among outbreaks might be ascribable to these differences in infectivity among FMDV strains. To investigate the molecular mechanisms underlying these differences, we estimated the infectivity of O/JPN/2000 and O/JPN/2010, which caused outbreaks of markedly different scales, in cell lines, Holstein cattle, and suckling mice. Viral growth of the two strains in cells was not remarkably different; however, O/JPN/2000 showed apparently low transmissibility in cattle. Mortality rates of suckling mice inoculated intraperitoneally with a 50% tissue culture infective dose (TCID50) of 10 for O/JPN/2000 and O/JPN/2010 also differed, at 0% and 100%, respectively. To identify genes responsible for this difference in infectivity, genetic regions of the full-length cDNA of O/JPN/2010 were replaced with corresponding fragments of O/JPN/2000. A total of eight recombinant viruses were successfully recovered, and suckling mice were intraperitoneally inoculated. Strikingly, recombinants having either VP1 or 3D derived from O/JPN/2000 showed 0% mortality in suckling mice, whereas other recombinants showed 100% mortality. This finding indicates that VP1, the outermost component of the virus particle, and 3D, an RNA-dependent RNA polymerase, are individually involved in the virulence of O/JPN/2010. Three-dimensional structural analysis of VP1 confirmed that amino acid differences between the two strains were located mainly at the domain interacting with the cellular receptor. On the other hand, measurement of their mutation frequencies demonstrated that O/JPN/2000 had higher replication fidelity than O/JPN/2010. IMPORTANCE Efforts to understand the universal mechanism of foot-and-mouth disease virus (FMDV) infection may be aided by knowledge of the molecular mechanisms which underlie differences in virulence beyond multiple topotypes and serotypes of FMDV. Here, we demonstrated independent genetic determinants of two FMDV isolates which have different transmissibility in cattle, namely, VP1 and 3D protein. Findings suggested that the selectivity of VP1 for host cell receptors and replication fidelity during replication were important individual factors in the induction of differences in virulence in the host as well as in the severity of outbreaks in the field. These findings will aid the development of safe live vaccines and antivirals which obstruct viral infection in natural hosts.Tatsuya NishiKazuki MoriokaNobuko SaitoMakoto YamakawaToru KannoKatsuhiko FukaiAmerican Society for Microbiologyarticlefoot-and-mouth disease virusgenetic determinantsvirulenceMicrobiologyQR1-502ENmSphere, Vol 4, Iss 4 (2019)
institution	DOAJ
collection	DOAJ
language	EN
topic	foot-and-mouth disease virus genetic determinants virulence Microbiology QR1-502
spellingShingle	foot-and-mouth disease virus genetic determinants virulence Microbiology QR1-502 Tatsuya Nishi Kazuki Morioka Nobuko Saito Makoto Yamakawa Toru Kanno Katsuhiko Fukai Genetic Determinants of Virulence between Two Foot-and-Mouth Disease Virus Isolates Which Caused Outbreaks of Differing Severity
description	ABSTRACT Individual foot-and-mouth disease virus (FMDV) strains reveal different degrees of infectivity and pathogenicity in host animals. The differences in severity among outbreaks might be ascribable to these differences in infectivity among FMDV strains. To investigate the molecular mechanisms underlying these differences, we estimated the infectivity of O/JPN/2000 and O/JPN/2010, which caused outbreaks of markedly different scales, in cell lines, Holstein cattle, and suckling mice. Viral growth of the two strains in cells was not remarkably different; however, O/JPN/2000 showed apparently low transmissibility in cattle. Mortality rates of suckling mice inoculated intraperitoneally with a 50% tissue culture infective dose (TCID50) of 10 for O/JPN/2000 and O/JPN/2010 also differed, at 0% and 100%, respectively. To identify genes responsible for this difference in infectivity, genetic regions of the full-length cDNA of O/JPN/2010 were replaced with corresponding fragments of O/JPN/2000. A total of eight recombinant viruses were successfully recovered, and suckling mice were intraperitoneally inoculated. Strikingly, recombinants having either VP1 or 3D derived from O/JPN/2000 showed 0% mortality in suckling mice, whereas other recombinants showed 100% mortality. This finding indicates that VP1, the outermost component of the virus particle, and 3D, an RNA-dependent RNA polymerase, are individually involved in the virulence of O/JPN/2010. Three-dimensional structural analysis of VP1 confirmed that amino acid differences between the two strains were located mainly at the domain interacting with the cellular receptor. On the other hand, measurement of their mutation frequencies demonstrated that O/JPN/2000 had higher replication fidelity than O/JPN/2010. IMPORTANCE Efforts to understand the universal mechanism of foot-and-mouth disease virus (FMDV) infection may be aided by knowledge of the molecular mechanisms which underlie differences in virulence beyond multiple topotypes and serotypes of FMDV. Here, we demonstrated independent genetic determinants of two FMDV isolates which have different transmissibility in cattle, namely, VP1 and 3D protein. Findings suggested that the selectivity of VP1 for host cell receptors and replication fidelity during replication were important individual factors in the induction of differences in virulence in the host as well as in the severity of outbreaks in the field. These findings will aid the development of safe live vaccines and antivirals which obstruct viral infection in natural hosts.
format	article
author	Tatsuya Nishi Kazuki Morioka Nobuko Saito Makoto Yamakawa Toru Kanno Katsuhiko Fukai
author_facet	Tatsuya Nishi Kazuki Morioka Nobuko Saito Makoto Yamakawa Toru Kanno Katsuhiko Fukai
author_sort	Tatsuya Nishi
title	Genetic Determinants of Virulence between Two Foot-and-Mouth Disease Virus Isolates Which Caused Outbreaks of Differing Severity
title_short	Genetic Determinants of Virulence between Two Foot-and-Mouth Disease Virus Isolates Which Caused Outbreaks of Differing Severity
title_full	Genetic Determinants of Virulence between Two Foot-and-Mouth Disease Virus Isolates Which Caused Outbreaks of Differing Severity
title_fullStr	Genetic Determinants of Virulence between Two Foot-and-Mouth Disease Virus Isolates Which Caused Outbreaks of Differing Severity
title_full_unstemmed	Genetic Determinants of Virulence between Two Foot-and-Mouth Disease Virus Isolates Which Caused Outbreaks of Differing Severity
title_sort	genetic determinants of virulence between two foot-and-mouth disease virus isolates which caused outbreaks of differing severity
publisher	American Society for Microbiology
publishDate	2019
url	https://doaj.org/article/de074b6356534f419d9bfc95923f03bf
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Genetic Determinants of Virulence between Two Foot-and-Mouth Disease Virus Isolates Which Caused Outbreaks of Differing Severity

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