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

机译:蛋白石停止密码子的破坏减弱基孔肯雅病毒引起的关节炎和病理。

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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.
机译:摘要基孔肯雅病毒(CHIKV)是一种由蚊子传播的甲病毒,在过去十年中引起了几次严重的使急性和慢性关节炎和关节痛致衰弱的事件。其中包括最近在加勒比海岛屿和美洲爆发的暴发,造成超过100万例病毒性关节痛病例。尽管CHIKV对全球健康有重大影响,但对导致CHIKV诱发疾病的病毒决定因素尚不完全了解。大多数CHIKV病毒株在病毒nsP3基因的末端均包含保守的蛋白石终止密码子。但是,已经描述了编码精氨酸密码子代替蛋白石终止密码子的CHIKV菌株,并且对来自加勒比海地区的CHIKV分离株的深度测序分析确定了该菌株中的精氨酸和蛋白石变体。因此,我们假设精氨酸突变的引入代替蛋白石终止密码子可能会影响CHIKV毒力。我们通过将精氨酸突变引入来自斯里兰卡的CHIKV株的特征明确的传染性克隆并将其命名为Opal524R进行了测试。这种突变不会损害体外或体内的病毒复制动力学。尽管如此,Opal524R病毒在感染小鼠的脚和脚踝内引起的肿胀,炎症和损伤明显减少。此外,与亲本菌株相比,我们观察到促炎性细胞因子和趋化因子的诱导延迟,以及CD4〜(+)T细胞和NK细胞募集减少。因此,蛋白石终止密码子在CHIKV发病机理中起着重要作用,而与对病毒复制的影响无关。重要说明基孔肯雅病毒(CHIKV)是一种由蚊子传播的alpha病毒,可引起病毒性关节痛的大量爆发。对CHIKV和其他alphaviruses的研究表明,nsP3中的蛋白石终止密码子是高度保守的。但是,一些CHIKV病毒株和其他α病毒在蛋白石终止密码子中包含突变。这些突变改变了哺乳动物和蚊子宿主中相关α病毒的毒力。在这里,我们报告从最近在加勒比海岛屿爆发的CHIKV株的临床分离株包含编码蛋白石终止密码子或精氨酸突变的病毒混合物。将蛋白石终止密码子突变为精氨酸残基可减弱CHIKV诱导的小鼠模型疾病。与含有蛋白石的亲本病毒感染相比,精氨酸突变体的感染导致有限的肿胀和炎症,并削弱了病理免疫免疫介质(包括CD4〜(+)T细胞和NK细胞)的募集。我们建议蛋白石终止密码子在诱导严重的CHIKV疾病中起重要作用。

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