Lung-brain communication in the onset of respiratory viral infection.

摘要 社会面临着来自呼吸道免疫挑战（包括呼吸道病毒感染）的日益增加的负担。 呼吸道病毒感染，包括甲型流感病毒，可导致脑功能变化;了解 肺和脑健康之间的联系对于预测我们社会不断变化的健康需求至关重要。肺 和大脑通过几种信号机制进行双向交流， 互相影响目前尚不清楚肺-脑通讯如何影响呼吸道病毒感染的进展。 感染，或者随着炎症反应的进展，不同的通信机制是如何优先的。 使用感染A型流感病毒株PR 8的小鼠模型，该提议探索了免疫系统中的免疫信号传导。 双向肺脑轴这项提议的首要目标是检验肺和 在呼吸道感染过程中，大脑发挥双向影响，改变彼此的免疫状态。我 初步数据显示，在PR 8感染期间，中枢神经系统（CNS）的变化发生在PR 8感染之前。 肺组织中炎性基因上调。影响这些快速CNS变化的信号机制 在神经元活动中的作用，以及这种CNS反应对感染进展的作用，仍然未知。 肺神经内分泌细胞（PNEC）是感觉细胞，在呼吸过程中产生免疫反应。 炎症性挑战这些细胞也是肺上皮中唯一直接受迷走神经支配的细胞 神经。尽管PNEC和迷走神经两者的免疫功能是已知的，但PNEC信号传导至神经元的作用仍然是未知的。 呼吸道感染期间的CNS仍然没有研究。在目标1中，我将探讨PNEC信号转导在 通过表征在感染期间来自这些细胞的分子和迷走神经信号传导来检测感染。然后我会切除这些 在calacre小鼠中使用cre依赖性AAV递送机制在PR 8感染前对细胞进行细胞内转染，以确定是否 它们的信号传导有助于外周或CNS对感染的反应。不管信号机制如何 启动对PR 8感染的快速CNS应答，这种应答的最终结果尚不清楚。 神经元系综可以编码免疫记忆，影响外周器官的免疫状态。在目标2中， 我将确定神经元活动如何影响小胶质细胞和外周免疫反应在整个PR 8 感染开始。使用高通量成像和机器学习分析管道，我将绘制神经元 和TRAP 2：：TdTom小鼠中小胶质细胞对PR 8感染的反应。然后我将探讨神经元活动的作用 通过使用TRAP 2：：hM 3Dq捕获并随后再激活在PR 8感染期间活跃的神经元群体 小鼠我将描述CNS组织中的小胶质细胞反应和外周免疫反应，以确定是否 PR 8反应性神经元群体的活性足以驱动免疫结果。总之，这 该提案将探讨肺和大脑健康之间的联系，重点是这些器官对每个人的影响。 呼吸道感染发病时的其他免疫状态。

ABSTRACT Society faces increasing burden from respiratory immune challenge including respiratory viral infection. Respiratory viral infection, including with influenza A virus, can cause changes in brain function; understanding the link between lung and brain health is critical to anticipating the shifting health needs of our society. The lung and brain engage in bidirectional communication through several signaling mechanisms, allowing these organs to influence each other. It is unknown how lung-brain communication impacts the progression of respiratory viral infection, or how different communication mechanisms are prioritized as inflammatory response progresses. Using a mouse model of infection with influenza A strain PR8, this proposal explores immune signaling in the bidirectional lung-brain axis. The overarching goal of this proposal is to test the hypothesis that the lung and brain exert bidirectional influence during respiratory infection, altering each other’s immune states. My preliminary data shows that during PR8 infection, changes in central nervous system (CNS) occur prior to inflammatory gene upregulation in lung tissue. The signaling mechanisms influencing these rapid CNS changes in neuronal activity, as well as the role of this CNS response on infection progression, remain unknown. Pulmonary neuroendocrine cells (PNECs) are sensory cells which mount an immune response during respiratory inflammatory challenge. These cells are also the only cells in the lung epithelium directly innervated by the vagus nerve. Despite the known immune function of both PNECs and the vagus nerve, the role of PNECs signaling to the CNS during a respiratory infection remains unstudied. In Aim 1, I will explore the role of PNEC signaling in infection by characterizing molecular and vagal signaling from these cells during infection. I will then ablate these cells prior to PR8 infection using a cre-dependent AAV delivery mechanism in calcacre mice to determine whether their signaling contributes to the peripheral or CNS response to infection. Regardless of signaling mechanisms initiating the rapid CNS response to PR8 infection, the ultimate consequence of this response is unknown. Neuronal ensembles can encode immune memory, impacting the immune states of peripheral organs. In Aim 2, I will determine how neuronal activity influences the microglial and peripheral immune response throughout PR8 infection onset. Using high-throughput imaging and a machine learning analysis pipeline, I will map the neuronal and microglial response to PR8 infection in TRAP2::TdTom mice. I will then explore the role of neuronal activity by capturing and later re-activating the neuronal population active during PR8 infection using TRAP2::hM3Dq mice. I will characterize microglial response in CNS tissue and peripheral immune response to determine if activity of the PR8-responsive neuronal population is sufficient to drive immune outcomes. Altogether, this proposal will explore the connection between lung and brain health, focusing on these organs’ influence on each other’s immune states in the onset of respiratory infection.