Analysis of the T Cell Response to Zika Virus and Identification of a Novel CD8+ T Cell Epitope in Immunocompetent Mice.
Analysis of the T Cell Response to Zika Virus and Identification of a Novel CD8+ T Cell Epitope in Immunocompetent Mice.
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DOI：
10.1371/journal.ppat.1006184
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发表时间：
2017-02
期刊：
影响因子：
6.7
通讯作者：
Richer MJ
中科院分区：
文献类型：
--
作者：
Pardy RD;Rajah MM;Condotta SA;Taylor NG;Sagan SM;Richer MJ
寨卡病毒（ZIKV）是黄病毒科一种新出现的虫媒病毒。尽管在健康成年人中，寨卡病毒感染通常症状轻微且具有自限性，但感染与诸如吉兰 - 巴雷综合征等神经系统症状有关，并且在胎儿小头畸形与孕期寨卡病毒感染之间已建立起因果联系。这些风险以及当前寨卡病毒大流行的规模，迫切需要开发动物模型来研究对寨卡病毒感染的免疫反应。先前的动物模型主要关注免疫功能低下小鼠的发病机制。在本研究中，我们提供了一个在野生型免疫健全的C57BL/6小鼠中寨卡病毒感染的模型，并对感染后的免疫反应进行了分析。我们评估了几种先天免疫细胞类型的激活情况，研究了针对寨卡病毒感染的T细胞反应的动力学、表型和功能。我们的结果表明，在野生型免疫健全的C57BL/6小鼠中，寨卡病毒感染症状轻微，发病率极低。我们的数据表明，在适应性反应达到峰值时，有抗原经历的CD4 + T细胞极化为Th1表型，有抗原经历的CD8 + T细胞呈现出活化的效应细胞表型，同时产生效应细胞因子和溶细胞分子。此外，我们在包膜蛋白中鉴定出一个新的寨卡病毒CD8 + T细胞表位，大多数应答细胞都能识别该表位。我们的模型提供了一个重要的参考点，这将有助于剖析流行的寨卡病毒株的多态性对免疫反应和寨卡病毒发病机制的影响。此外，寨卡病毒表位的鉴定将有助于设计四聚体来研究表位特异性T细胞反应，并将对寨卡病毒疫苗策略的设计和开发具有重要意义。
寨卡病毒（ZIKV）是黄病毒科一种由蚊子传播的人类病原体。最值得注意的是，它导致了美洲正在发生的疫情，并与胎儿小头畸形等出生缺陷有因果关联。这些因素导致迫切需要小动物模型，可用于研究寨卡病毒感染、发病机制以及抗病毒免疫反应。到目前为止，开发的大多数小鼠模型都使用了缺乏健全免疫系统的小鼠。这些模型非常适合描述病毒的感染和发病机制，但无法对寨卡病毒感染的免疫反应进行全面分析，而这对于设计有效的疫苗策略是有用的。在此，我们证明寨卡病毒能够感染野生型免疫健全的C57BL/6小鼠，导致先天免疫反应的激活以及抗病毒T细胞反应的诱导。我们还在寨卡病毒包膜蛋白中鉴定出一个可被CD8 + T细胞识别的新表位。我们的模型为寨卡病毒感染的T细胞反应提供了一个重要的参考点，这将有助于比较分析，并对有效疫苗的设计和开发具有影响。
Zika virus (ZIKV) is an emerging arbovirus of the Flaviviridae family. Although ZIKV infection is typically mild and self-limiting in healthy adults, infection has been associated with neurological symptoms such as Guillain-Barré syndrome, and a causal link has been established between fetal microcephaly and ZIKV infection during pregnancy. These risks, and the magnitude of the ongoing ZIKV pandemic, have created an urgent need for the development of animal models to study the immune response to ZIKV infection. Previous animal models have primarily focused on pathogenesis in immunocompromised mice. In this study, we provide a model of ZIKV infection in wild-type immunocompetent C57BL/6 mice, and have provided an analysis of the immune response to infection. We evaluated the activation of several innate immune cell types, and studied the kinetics, phenotype, and functionality of T cell responses to ZIKV infection. Our results demonstrate that ZIKV infection is mild in wild-type immunocompetent C57BL/6 mice, resulting in minimal morbidity. Our data establish that at the peak of the adaptive response, antigen-experienced CD4+ T cells polarize to a Th1 phenotype, and antigen-experienced CD8+ T cells exhibit an activated effector phenotype, producing both effector cytokines and cytolytic molecules. Furthermore, we have identified a novel ZIKV CD8+ T cell epitope in the envelope protein that is recognized by the majority of responding cells. Our model provides an important reference point that will help dissect the impact of polymorphisms in the circulating ZIKV strains on the immune response and ZIKV pathogenesis. In addition, the identification of a ZIKV epitope will allow for the design of tetramers to study epitope-specific T cell responses, and will have important implications for the design and development of ZIKV vaccine strategies. Zika virus (ZIKV) is a mosquito-borne human pathogen of the Flaviviridae family. Most notably, it is responsible for an ongoing epidemic in the Americas, and has been causally linked to birth defects such as fetal microcephaly. These factors have led to an urgent need for small animal models, which may be used to study ZIKV infection, pathogenesis, and the antiviral immune response. To date, the majority of mouse models developed have used mice that lack a competent immune system. These models are excellent for characterizing infection and the pathogenesis of the virus, but are unable to provide a comprehensive analysis of the immune response to ZIKV infection, which will be useful for the design of effective vaccine strategies. Herein, we demonstrate that ZIKV is able to infect wild-type immunocompetent C57BL/6 mice, resulting in activation of the innate immune response and induction of an antiviral T cell response. We have also identified a novel epitope recognized by CD8+ T cells within the ZIKV envelope protein. Our model provides an important reference point regarding the T cell response to ZIKV infection, which will be useful in comparative analyses and will have implications in the design and development of effective vaccines.