T cells promote microglia-mediated synaptic elimination and cognitive dysfunction during recovery from neuropathogenic flaviviruses
T cells promote microglia-mediated synaptic elimination and cognitive dysfunction during recovery from neuropathogenic flaviviruses
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DOI：
10.1038/s41593-019-0427-y
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发表时间：
2019-08-01
影响因子：
25
通讯作者：
Klein, Robyn S.
中科院分区：
文献类型：
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作者：
Garber, Charise;Soung, Allison;Klein, Robyn S.
T细胞从CNS清除病毒，并通过细胞因子信号传导动态调节脑功能，包括空间学习。在这里，我们确定了西尼罗河病毒（WNV）或寨卡病毒（ZIKV）感染恢复后持续存在的海马T细胞是否会影响海马依赖性学习和记忆。使用新建立的成年动物病毒性脑炎恢复模型，我们表明，在从WNV或ZIKV感染中恢复的小鼠中，小胶质细胞中的T细胞源性干扰素-γ（IFN-γ）信号转导通过病毒靶向特异性机制成为空间学习缺陷的基础。从WNV感染恢复后，小鼠显示突触前末端消除，缺乏修复，而对于ZIKV，小鼠显示广泛的神经元凋亡，突触后末端丢失。因此，在小胶质细胞中缺乏CD 8（+）T细胞或IFN-γ信号传导的动物证明了在WNV感染后对突触消除的保护，并且在ZIKV感染后随着突触恢复减少神经元凋亡。因此，向小胶质细胞的T细胞信号传导驱动与新兴嗜神经黄病毒相关的感染后认知后遗症。
T cells clear virus from the CNS and dynamically regulate brain functions, including spatial learning, through cytokine signaling. Here we determined whether hippocampal T cells that persist after recovery from infection with West Nile virus (WNV) or Zika virus (ZIKV) impact hippocampal-dependent learning and memory. Using newly established models of viral encephalitis recovery in adult animals, we show that in mice that have recovered from WNV or ZIKV infection, T cell-derived interferon-gamma (IFN-gamma) signaling in microglia underlies spatial-learning defects via virus-target-specific mechanisms. Following recovery from WNV infection, mice showed presynaptic termini elimination with lack of repair, while for ZIKV, mice showed extensive neuronal apoptosis with loss of postsynaptic termini. Accordingly, animals deficient in CD8(+) T cells or IFN-gamma signaling in microglia demonstrated protection against synapse elimination following WNV infection and decreased neuronal apoptosis with synapse recovery following ZIKV infection. Thus, T cell signaling to microglia drives post-infectious cognitive sequelae that are associated with emerging neurotropic flaviviruses.