Zika (PRVABC59) Infection Is Associated with T cell Infiltration and Neurodegeneration in CNS of Immunocompetent Neonatal C57Bl/6 Mice.
Zika (PRVABC59) Infection Is Associated with T cell Infiltration and Neurodegeneration in CNS of Immunocompetent Neonatal C57Bl/6 Mice.
复制标题
DOI：
10.1371/journal.ppat.1006004
复制
发表时间：
2016-11
期刊：
影响因子：
6.7
通讯作者：
Verthelyi D
中科院分区：
文献类型：
--
作者：
Manangeeswaran M;Ireland DD;Verthelyi D
寨卡病毒（ZIKV）最近的传播及其与格林巴利病和其他神经系统疾病以及包括小头畸形在内的先天性缺陷发病率上升的关系，迫切需要开发动物模型，以检查该疾病的发病机制，并探索潜在治疗方法和疫苗的功效。最近开发的寨卡病毒感染模型利用干扰素反应缺陷的小鼠。在这项研究中，我们用免疫功能正常的新生C57BL/6小鼠建立了一种新的外周寨卡病毒感染模型，并对其临床进展、病毒分布、免疫反应和神经病理学与C57BL/6- ifnar KO小鼠进行了比较。我们发现，ZIKV感染的IFNAR KO小鼠出现双侧后肢瘫痪并在感染后5-6天死亡，而免疫正常的B6 WT小鼠在感染后13天出现神经系统疾病的症状，包括步态不稳、运动性震颤、严重共济失调和癫痫发作，并在2周内逐渐消退。免疫组化显示病毒抗原在两种模型的疾病高峰期主要集中在小脑。然而，IFNAR KO小鼠表现出中性粒细胞和巨噬细胞的浸润以及IL-1、IL-6和Cox2的较高表达，而B6 WT小鼠表现出以T细胞为主的中枢神经系统细胞浸润，特别是CD8+ T细胞，并且在疾病高峰期IFNg、GzmB和Prf1 mRNA表达水平升高。最后，B6 WT小鼠的中枢神经系统显示神经退行性变主要发生在小脑，而在缺乏IFN反应的小鼠中不那么突出，这可能是由于该模型中细胞浸润的差异和疾病的快速进展。开发寨卡病毒感染的B6 WT模型将有助于深入了解该病毒的免疫病理学，并有助于评估可能的治疗方法和疫苗。寨卡病毒（ZIKV）最近的传播及其与神经系统疾病和先天性缺陷发生率上升的关联，迫切需要动物模型来检查该疾病的发病机制，并探索潜在治疗方法和疫苗的功效。我们描述了免疫功能正常的B6 WT小鼠的第一个症状性PRVABC59（ZIKV）动物模型，显示1日龄小鼠皮下攻击导致非致死性神经系统疾病，其特征是步态不稳，运动性震颤，严重的共济失调和癫痫发作，2周后消退。寨卡病毒感染小鼠小脑神经元，诱导淋巴细胞向大脑浸润。免疫反应保护小鼠免于死亡，但也可能导致神经退行性变，因为干扰素反应有缺陷的小鼠大脑和周围器官的病毒载量增加，在5-6天内死亡，但神经退行性变的迹象较少。该小鼠模型绕过经胎盘传播和随后的胎盘功能不全，将有助于详细研究疾病的发病机制以及可能的治疗方法和疫苗的机制研究。最后，它的非致命性结果允许研究评估感染的长期影响，并探索可能导致疾病再激活的条件。
The recent spread of Zika virus (ZIKV) and its association with increased rates of Guillain Barre and other neurological disorders as well as congenital defects that include microcephaly has created an urgent need to develop animal models to examine the pathogenesis of the disease and explore the efficacy of potential therapeutics and vaccines. Recently developed infection models for ZIKV utilize mice defective in interferon responses. In this study we establish and characterize a new model of peripheral ZIKV infection using immunocompetent neonatal C57BL/6 mice and compare its clinical progression, virus distribution, immune response, and neuropathology with that of C57BL/6-IFNAR KO mice. We show that while ZIKV infected IFNAR KO mice develop bilateral hind limb paralysis and die 5–6 days post-infection (dpi), immunocompetent B6 WT mice develop signs of neurological disease including unsteady gait, kinetic tremors, severe ataxia and seizures by 13 dpi that subside gradually over 2 weeks. Immunohistochemistry show viral antigen predominantly in cerebellum at the peak of the disease in both models. However, whereas IFNAR KO mice showed infiltration by neutrophils and macrophages and higher expression of IL-1, IL-6 and Cox2, B6 WT mice show a cellular infiltration in the CNS composed predominantly of T cells, particularly CD8+ T cells, and increased mRNA expression levels of IFNg, GzmB and Prf1 at peak of disease. Lastly, the CNS of B6 WT mice shows evidence of neurodegeneration predominantly in the cerebellum that are less prominent in mice lacking the IFN response possibly due to the difference in cellular infiltrates and rapid progression of the disease in that model. The development of the B6 WT model of ZIKV infection will provide insight into the immunopathology of the virus and facilitate assessments of possible therapeutics and vaccines. The recent spread of Zika virus (ZIKV) and its association with increased rates of neurological disorders and congenital defects created an urgent need for animal models to examine the pathogenesis of the disease and explore the efficacy of potential therapeutics and vaccines. We describe the first symptomatic PRVABC59(ZIKV) animal model in immunocompetent B6 WT mice showing that a subcutaneous challenge in 1 day old mice leads to non-lethal neurological disease that is characterized by unsteady gait, kinetic tremors, severe ataxia and seizures that subsides after 2 weeks. ZIKV infects neurons in cerebellum of mice and elicits the infiltration of lymphocytes into the brain. The immune response protects mice from death but may also contribute to neurodegeneration as mice with defective interferon responses have increased virus loads in brain and peripheral organs, succumbing to the disease in 5–6 days, but have fewer signs of neurodegeneration. This mouse model bypasses transplacental transmission and consequent placental insufficiency and will facilitate detailed investigations into the pathogenesis of the disease as well as mechanistic studies for possible therapeutics and vaccines. Lastly, its non-lethal outcome allows for studies assessing the long term effects of the infection, and exploring conditions that could lead to disease reactivation.
登录
查看更多内容
影响因子：
3.8
作者：
Dowall SD;Graham VA;Rayner E;Atkinson B;Hall G;Watson RJ;Bosworth A;Bonney LC;Kitchen S;Hewson R
通讯作者：
Hewson R
影响因子：
6.7
作者：
Chang TH;Kubota T;Matsuoka M;Jones S;Bradfute SB;Bray M;Ozato K
通讯作者：
Ozato K
日本脑炎病毒激活自噬作为病毒免疫逃避策略
影响因子：
3.7
作者：
Jin R;Zhu W;Cao S;Chen R;Jin H;Liu Y;Wang S;Wang W;Xiao G
通讯作者：
Xiao G
影响因子：
3.3
作者：
Kulcsar, Kirsten A.;Griffin, Diane E.
通讯作者：
Griffin, Diane E.
DOI：
10.1007/bf01249709
发表时间：
1971-01-01
期刊：
ARCHIV FUR DIE GESAMTE VIRUSFORSCHUNG
影响因子：
--
作者：
BELL, TM;FIELD, EJ;NARANG, HK
通讯作者：
NARANG, HK