Disruption of the Opal Stop Codon Attenuates Chikungunya Virus-Induced Arthritis and Pathology

ABSTRACT Chikungunya virus (CHIKV) is a mosquito-borne alphavirus responsible for several significant outbreaks of debilitating acute and chronic arthritis and arthralgia over the past decade. These include a recent outbreak in the Caribbean islands and the Americas that caused more than 1 million c...

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Autores principales:	Jennifer E. Jones, Kristin M. Long, Alan C. Whitmore, Wes Sanders, Lance R. Thurlow, Julia A. Brown, Clayton R. Morrison, Heather Vincent, Kayla M. Peck, Christian Browning, Nathaniel Moorman, Jean K. Lim, Mark T. Heise
Formato:	article
Lenguaje:	EN
Publicado:	American Society for Microbiology 2017
Materias:	alphavirus chikungunya opal stop codon viral pathogenesis Microbiology QR1-502
Acceso en línea:	https://doaj.org/article/8f27fe69f5174573bc32b852d1bbb70e
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spelling	oai:doaj.org-article:8f27fe69f5174573bc32b852d1bbb70e2021-11-15T15:51:55ZDisruption of the Opal Stop Codon Attenuates Chikungunya Virus-Induced Arthritis and Pathology10.1128/mBio.01456-172150-7511https://doaj.org/article/8f27fe69f5174573bc32b852d1bbb70e2017-12-01T00:00:00Zhttps://journals.asm.org/doi/10.1128/mBio.01456-17https://doaj.org/toc/2150-7511ABSTRACT Chikungunya virus (CHIKV) is a mosquito-borne alphavirus responsible for several significant outbreaks of debilitating acute and chronic arthritis and arthralgia over the past decade. These include a recent outbreak in the Caribbean islands and the Americas that caused more than 1 million cases of viral arthralgia. Despite the major impact of CHIKV on global health, viral determinants that promote CHIKV-induced disease are incompletely understood. Most CHIKV strains contain a conserved opal stop codon at the end of the viral nsP3 gene. However, CHIKV strains that encode an arginine codon in place of the opal stop codon have been described, and deep-sequencing analysis of a CHIKV isolate from the Caribbean identified both arginine and opal variants within this strain. Therefore, we hypothesized that the introduction of the arginine mutation in place of the opal termination codon may influence CHIKV virulence. We tested this by introducing the arginine mutation into a well-characterized infectious clone of a CHIKV strain from Sri Lanka and designated this virus Opal524R. This mutation did not impair viral replication kinetics in vitro or in vivo. Despite this, the Opal524R virus induced significantly less swelling, inflammation, and damage within the feet and ankles of infected mice. Further, we observed delayed induction of proinflammatory cytokines and chemokines, as well as reduced CD4+ T cell and NK cell recruitment compared to those in the parental strain. Therefore, the opal termination codon plays an important role in CHIKV pathogenesis, independently of effects on viral replication. IMPORTANCE Chikungunya virus (CHIKV) is a mosquito-borne alphavirus that causes significant outbreaks of viral arthralgia. Studies with CHIKV and other alphaviruses demonstrated that the opal termination codon within nsP3 is highly conserved. However, some strains of CHIKV and other alphaviruses contain mutations in the opal termination codon. These mutations alter the virulence of related alphaviruses in mammalian and mosquito hosts. Here, we report that a clinical isolate of a CHIKV strain from the recent outbreak in the Caribbean islands contains a mixture of viruses encoding either the opal termination codon or an arginine mutation. Mutating the opal stop codon to an arginine residue attenuates CHIKV-induced disease in a mouse model. Compared to infection with the opal-containing parental virus, infection with the arginine mutant causes limited swelling and inflammation, as well as dampened recruitment of immune mediators of pathology, including CD4+ T cells and NK cells. We propose that the opal termination codon plays an essential role in the induction of severe CHIKV disease.Jennifer E. JonesKristin M. LongAlan C. WhitmoreWes SandersLance R. ThurlowJulia A. BrownClayton R. MorrisonHeather VincentKayla M. PeckChristian BrowningNathaniel MoormanJean K. LimMark T. HeiseAmerican Society for Microbiologyarticlealphaviruschikungunyaopal stop codonviral pathogenesisMicrobiologyQR1-502ENmBio, Vol 8, Iss 6 (2017)
institution	DOAJ
collection	DOAJ
language	EN
topic	alphavirus chikungunya opal stop codon viral pathogenesis Microbiology QR1-502
spellingShingle	alphavirus chikungunya opal stop codon viral pathogenesis Microbiology QR1-502 Jennifer E. Jones Kristin M. Long Alan C. Whitmore Wes Sanders Lance R. Thurlow Julia A. Brown Clayton R. Morrison Heather Vincent Kayla M. Peck Christian Browning Nathaniel Moorman Jean K. Lim Mark T. Heise Disruption of the Opal Stop Codon Attenuates Chikungunya Virus-Induced Arthritis and Pathology
description	ABSTRACT Chikungunya virus (CHIKV) is a mosquito-borne alphavirus responsible for several significant outbreaks of debilitating acute and chronic arthritis and arthralgia over the past decade. These include a recent outbreak in the Caribbean islands and the Americas that caused more than 1 million cases of viral arthralgia. Despite the major impact of CHIKV on global health, viral determinants that promote CHIKV-induced disease are incompletely understood. Most CHIKV strains contain a conserved opal stop codon at the end of the viral nsP3 gene. However, CHIKV strains that encode an arginine codon in place of the opal stop codon have been described, and deep-sequencing analysis of a CHIKV isolate from the Caribbean identified both arginine and opal variants within this strain. Therefore, we hypothesized that the introduction of the arginine mutation in place of the opal termination codon may influence CHIKV virulence. We tested this by introducing the arginine mutation into a well-characterized infectious clone of a CHIKV strain from Sri Lanka and designated this virus Opal524R. This mutation did not impair viral replication kinetics in vitro or in vivo. Despite this, the Opal524R virus induced significantly less swelling, inflammation, and damage within the feet and ankles of infected mice. Further, we observed delayed induction of proinflammatory cytokines and chemokines, as well as reduced CD4+ T cell and NK cell recruitment compared to those in the parental strain. Therefore, the opal termination codon plays an important role in CHIKV pathogenesis, independently of effects on viral replication. IMPORTANCE Chikungunya virus (CHIKV) is a mosquito-borne alphavirus that causes significant outbreaks of viral arthralgia. Studies with CHIKV and other alphaviruses demonstrated that the opal termination codon within nsP3 is highly conserved. However, some strains of CHIKV and other alphaviruses contain mutations in the opal termination codon. These mutations alter the virulence of related alphaviruses in mammalian and mosquito hosts. Here, we report that a clinical isolate of a CHIKV strain from the recent outbreak in the Caribbean islands contains a mixture of viruses encoding either the opal termination codon or an arginine mutation. Mutating the opal stop codon to an arginine residue attenuates CHIKV-induced disease in a mouse model. Compared to infection with the opal-containing parental virus, infection with the arginine mutant causes limited swelling and inflammation, as well as dampened recruitment of immune mediators of pathology, including CD4+ T cells and NK cells. We propose that the opal termination codon plays an essential role in the induction of severe CHIKV disease.
format	article
author	Jennifer E. Jones Kristin M. Long Alan C. Whitmore Wes Sanders Lance R. Thurlow Julia A. Brown Clayton R. Morrison Heather Vincent Kayla M. Peck Christian Browning Nathaniel Moorman Jean K. Lim Mark T. Heise
author_facet	Jennifer E. Jones Kristin M. Long Alan C. Whitmore Wes Sanders Lance R. Thurlow Julia A. Brown Clayton R. Morrison Heather Vincent Kayla M. Peck Christian Browning Nathaniel Moorman Jean K. Lim Mark T. Heise
author_sort	Jennifer E. Jones
title	Disruption of the Opal Stop Codon Attenuates Chikungunya Virus-Induced Arthritis and Pathology
title_short	Disruption of the Opal Stop Codon Attenuates Chikungunya Virus-Induced Arthritis and Pathology
title_full	Disruption of the Opal Stop Codon Attenuates Chikungunya Virus-Induced Arthritis and Pathology
title_fullStr	Disruption of the Opal Stop Codon Attenuates Chikungunya Virus-Induced Arthritis and Pathology
title_full_unstemmed	Disruption of the Opal Stop Codon Attenuates Chikungunya Virus-Induced Arthritis and Pathology
title_sort	disruption of the opal stop codon attenuates chikungunya virus-induced arthritis and pathology
publisher	American Society for Microbiology
publishDate	2017
url	https://doaj.org/article/8f27fe69f5174573bc32b852d1bbb70e
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Disruption of the Opal Stop Codon Attenuates Chikungunya Virus-Induced Arthritis and Pathology

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