Department of Pathology, Microbiology and Immunology, School of Veterinary Medicine, University of California, Davis, California, USA.
Department of Pathology, Microbiology and Immunology, School of Veterinary Medicine, University of California, Davis, California, USA
J Virol. 2019 Jan 17;93(3). doi: 10.1128/JVI.01606-18. Print 2019 Feb 1.
Chikungunya virus (CHIKV) is a reemerging global health threat that produces debilitating arthritis in people. Like other RNA viruses with high mutation rates, CHIKV produces populations of genetically diverse genomes within a host. While several known CHIKV mutations influence disease severity in vertebrates and transmission by mosquitoes, the role of intrahost diversity in chikungunya arthritic disease has not been studied. In this study, high- and low-fidelity CHIKV variants, previously characterized by altered population mutation frequencies, were used to evaluate how intrahost diversity influences clinical disease, CHIKV replication, and antibody neutralization in immunocompetent adult mice inoculated in the rear footpads. Both high- and low-fidelity mutations were hypothesized to attenuate CHIKV arthritic disease, replication, and neutralizing antibody levels compared to wild-type (WT) CHIKV. Unexpectedly, high-fidelity mutants elicited more severe arthritic disease than the WT despite comparable CHIKV replication, whereas a low-fidelity mutant produced attenuated disease and replication. Serum antibody developed against both high- and low-fidelity CHIKV exhibited reduced neutralization of WT CHIKV. Using next-generation sequencing (NGS), the high-fidelity mutations were demonstrated to be genetically stable but produced more genetically diverse populations than WT CHIKV in mice. This enhanced diversification was subsequently reproduced after serial passage. The NGS results contrast with previously reported population diversities for fidelity variants, which focused mainly on part of the E1 gene, and highlight the need for direct measurements of mutation rates to clarify CHIKV fidelity phenotypes. CHIKV is a reemerging global health threat that elicits debilitating arthritis in humans. There are currently no commercially available CHIKV vaccines. Like other RNA viruses, CHIKV has a high mutation rate and is capable of rapid intrahost diversification during an infection. In other RNA viruses, virus population diversity associates with disease progression; however, potential impacts of intrahost viral diversity on CHIKV arthritic disease have not been studied. Using previously characterized CHIKV fidelity variants, we addressed whether CHIKV population diversity influences the severity of arthritis and host antibody response in an arthritic mouse model. Our findings show that CHIKV populations with greater genetic diversity can cause more severe disease and stimulate antibody responses with reduced neutralization of low-diversity virus populations The discordant high-fidelity phenotypes in this study highlight the complexity of inferring replication fidelity indirectly from population diversity.
基孔肯雅病毒（CHIKV）是一种重新出现的全球健康威胁，会导致人类出现衰弱性关节炎。与其他具有高突变率的 RNA 病毒一样，CHIKV 在宿主内产生遗传多样性的病毒种群。虽然已经有几个已知的 CHIKV 突变会影响脊椎动物的疾病严重程度和蚊子的传播，但宿主内多样性在基孔肯雅关节炎疾病中的作用尚未得到研究。在这项研究中，先前通过改变种群突变频率进行了特征描述的高保真度和低保真度 CHIKV 变体被用于评估宿主内多样性如何影响免疫功能正常的成年小鼠后脚掌接种后的临床疾病、CHIKV 复制和抗体中和作用。高保真度和低保真度突变都被假设会导致 CHIKV 关节炎疾病、复制和中和抗体水平减弱，与野生型（WT）CHIKV 相比。出乎意料的是，尽管 CHIKV 复制相当，但高保真度突变体引起的关节炎疾病比 WT 更严重，而低保真度突变体则导致疾病和复制减弱。针对高保真度和低保真度 CHIKV 产生的血清抗体显示对 WT CHIKV 的中和作用降低。使用下一代测序（NGS），在小鼠中，高保真度突变被证明是遗传稳定的，但比 WT CHIKV 产生更多遗传多样性的种群。这种增强的多样化在连续传代后得到了重现。NGS 结果与以前主要集中在 E1 基因部分的保真度变体的种群多样性报告形成对比，突出了需要直接测量突变率以澄清 CHIKV 保真度表型的必要性。CHIKV 是一种重新出现的全球健康威胁，会导致人类出现衰弱性关节炎。目前尚无市售的 CHIKV 疫苗。与其他 RNA 病毒一样，CHIKV 具有很高的突变率，并且能够在感染过程中快速进行宿主内多样化。在其他 RNA 病毒中，病毒种群多样性与疾病进展相关；然而，宿主内病毒多样性对 CHIKV 关节炎疾病的潜在影响尚未得到研究。使用先前特征描述的 CHIKV 保真度变体，我们研究了 CHIKV 种群多样性是否会影响关节炎小鼠模型中关节炎的严重程度和宿主抗体反应。我们的研究结果表明，遗传多样性更大的 CHIKV 种群可能导致更严重的疾病，并刺激抗体反应，对低多样性病毒种群的中和作用降低。本研究中不一致的高保真度表型突出了从种群多样性间接推断复制保真度的复杂性。
