"Survivor" neurons drive persistent inflammation following West Nile virus infection

项目摘要/摘要-西尼罗河术后“幸存者”神经元驱动持续性炎症 病毒感染 西尼罗河病毒(West Nile Virus，WNV)是一种蚊媒黄病毒，可感染中枢神经元 系统。两名人类患者都是在神经侵袭性西尼罗河病毒展示学习中幸存下来的小鼠模型生物， 在病毒清除后持续很长时间的记忆和运动后遗症。虽然这些后遗症一直是 与中枢神经系统内的持续性炎症有关，这种炎症的来源仍然存在 默默无闻。我们小组和其他人之前的研究表明，神经元对 对包括病毒感染在内的多种应激源的程序性细胞死亡。这一观察将我们引向 假设感染了西尼罗河病毒的神经元存活并清除了感染--“存活的”神经元-- 维持病毒诱导的变化，推动长期炎症和中枢神经系统功能障碍。我们试图测试 这个想法是通过创建一个表达Cre重组酶的西尼罗河病毒的重组克隆，然后使用这种病毒来 在感染西尼罗河病毒的小鼠的大脑中标记“幸存的”神经元。这些细胞的空间转录分析 据透露，在病毒感染后的几周内，“幸存者”神经元仍保持着强烈的炎症信号 通过了。令人惊讶的是，在相同组织中相邻的WNV-幼稚神经元中没有这个特征， 支持“幸存”神经元是持续性中枢神经系统炎症的驱动因素的观点。这项工作的目标 这里提出的是使用这个新开发的模型来首先了解“幸存”神经元的变化 这推动了持续的炎症，其次是评估这种炎症反应的后果 这些神经元的功能，附近的细胞，以及生物的学习和记忆。我们建议 这些新模型和新兴技术的使用将提供对中枢神经系统功能障碍的重要洞察 由西尼罗河病毒感染引起。我们进一步认为，这一观点可能适用于病毒诱导的长期 其他环境中的炎症性功能障碍。

Project Summary/Abstract- “Survivor” neurons drive persistent inflammation following West Nile virus infection West Nile virus (WNV) is mosquito-borne flavivirus that can infect neurons of the central nervous system. Both human patients murine model organisms that survive neuroinvasive WNV display learning, memory and motor sequelae that persist long after the virus is cleared. While these sequelae have been associated with persistent inflammation within the CNS, the source of this inflammation has remained obscure. Previous studies by our group and others have revealed that neurons are remarkably resistant to programmed cell death in response to multiple stressors, including viral infection. This observation led us to hypothesize that neurons that are infected with WNV but survive and clear infection—“survivor” neurons— sustain virus-induced changes that drive long-term inflammation and CNS disfunction. We sought to test this idea by creating a recombinant clone of WNV that expresses Cre recombinase, then using this virus to mark “survivor” neurons in the brains of WNV-infected mice. Spatial transcriptomic analysis of these cells revealed that “survivor” neurons maintain a robust inflammatory signature weeks after viral infection is cleared. Strikingly, this signature is absent in adjacent, WNV-naïve neurons within the same tissues, supporting the idea that “survivor” neurons are drivers of persistent CNS inflammation. The goal of the work proposed here is to use this newly-developed model to first understand the changes to “survivor” neurons that drive persistent inflammation, and second to assess the consequences of this inflammatory response on the function of these neurons, on nearby cells and on organismal learning and memory. We suggest that the use of these new models and emerging technologies will provide important insight into CNS disfunction caused by WNV infection. We further suggest that this insight may be applicable to long-term virus-induced inflammatory dysfunction in other settings.