Analysis of the T Cell Response to Zika Virus and Identification of a Novel CD8+ T Cell Epitope in Immunocompetent Mice

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.

寨卡病毒（Zika virus, ZIKV）是黄病毒科（Flaviviridae）的一种新发虫媒病毒。尽管健康成人感染寨卡病毒后通常症状轻微且呈自限性，但该病毒感染已被证实与吉兰-巴雷综合征（Guillain-Barré syndrome）等神经系统症状相关，且妊娠期间感染寨卡病毒与胎儿小头畸形之间已确立因果关联。此类感染风险以及当前寨卡病毒大流行的规模，使得开发用于研究寨卡病毒感染免疫应答的动物模型成为迫切需求。既往动物模型主要聚焦于免疫缺陷小鼠的病毒致病机制。本研究构建了野生型免疫健全C57BL/6小鼠的寨卡病毒感染模型，并对感染后的免疫应答进行了分析。我们评估了多种先天免疫细胞的活化状态，并研究了寨卡病毒感染后T细胞应答的动力学特征、表型及功能。研究结果显示，野生型免疫健全C57BL/6小鼠感染寨卡病毒后症状轻微，仅出现极轻微的发病症状。本研究数据证实，在适应性免疫应答峰值阶段，抗原致敏的CD4+ T细胞会极化为辅助性T细胞1型（Th1）表型，而抗原致敏的CD8+ T细胞则呈现活化的效应表型，可同时分泌效应细胞因子与溶细胞分子。此外，我们在包膜蛋白（envelope protein）中发现了一种新型寨卡病毒CD8+ T细胞表位，该表位可被多数应答性T细胞识别。本模型为解析流行寨卡病毒毒株的多态性对免疫应答及寨卡病毒致病机制的影响提供了重要参考依据。此外，寨卡病毒表位的鉴定可用于构建四聚体（tetramer）以研究表位特异性T细胞应答，同时对寨卡病毒疫苗策略的设计与开发具有重要指导意义。