A novel Zika virus mouse model reveals strain specific differences in virus pathogenesis and host inflammatory immune responses

Zika virus (ZIKV) is a mosquito borne flavivirus, which was a neglected tropical pathogen until it emerged and spread across the Pacific Area and the Americas, causing large human outbreaks associated with fetal abnormalities and neurological disease in adults. The factors that contributed to the emergence, spread and change in pathogenesis of ZIKV are not understood. We previously reported that ZIKV evades cellular antiviral responses by targeting STAT2 for degradation in human cells. In this study, we demonstrate that Stat2-/- mice are highly susceptible to ZIKV infection, recapitulate virus spread to the central nervous system (CNS), gonads and other visceral organs, and display neurological symptoms. Further, we exploit this model to compare ZIKV pathogenesis caused by a panel of ZIKV strains of a range of spatiotemporal history of isolation and representing African and Asian lineages. We observed that African ZIKV strains induce short episodes of severe neurological symptoms followed by lethality. In comparison, Asian strains manifest prolonged signs of neuronal malfunctions, occasionally causing death of the Stat2-/- mice. African ZIKV strains induced higher levels of inflammatory cytokines and markers associated with cellular infiltration in the infected brain in mice, which may explain exacerbated pathogenesis in comparison to those of the Asian lineage. Interestingly, viral RNA levels in different organs did not correlate with the pathogenicity of the different strains. Taken together, we have established a new murine model that supports ZIKV infection and demonstrate its utility in highlighting intrinsic differences in the inflammatory response induced by different ZIKV strains leading to severity of disease. This study paves the way for the future interrogation of strain-specific changes in the ZIKV genome and their contribution to viral pathogenesis.

寨卡病毒（Zika virus, ZIKV）是一种蚊媒黄病毒，曾为一类被忽视的热带病原体，直至其在太平洋地区及美洲出现并扩散，引发大规模人类暴发疫情，关联胎儿畸形与成人神经系统疾病。目前，学界尚不明确寨卡病毒出现、扩散及致病机制改变的相关诱因。我们此前曾报道，寨卡病毒可通过靶向降解人源细胞中的信号转导与转录激活因子2（STAT2）以逃逸细胞抗病毒免疫应答。本研究中，我们证实STAT2基因敲除（Stat2-/-）小鼠对寨卡病毒感染高度易感，可重现病毒扩散至中枢神经系统（central nervous system, CNS）、性腺及其他内脏器官的过程，并出现神经系统症状。随后，我们利用该模型，对一组具有不同时空分离背景、分别代表非洲和亚洲进化分支的寨卡病毒毒株所引发的致病机制开展比较分析。结果显示，非洲型寨卡病毒毒株会引发短期严重神经系统症状，随后导致小鼠死亡；相较而言，亚洲型毒株会引发持续时间更长的神经功能异常表征，仅偶尔导致STAT2基因敲除小鼠死亡。非洲型寨卡病毒毒株可在感染小鼠的脑组织中诱导更高水平的炎症细胞因子及细胞浸润相关标志物，这或可解释其相较于亚洲型进化分支毒株更严重的致病表型。值得注意的是，不同器官中的病毒RNA载量与不同毒株的致病力并无关联。综上，我们成功构建了可支持寨卡病毒感染的新型小鼠模型，并证实该模型可用于揭示不同寨卡病毒毒株诱导的炎症应答的内在差异，进而阐明疾病严重程度的差异机制。本研究为后续探究寨卡病毒基因组的毒株特异性变异及其对病毒致病机制的影响奠定了基础。