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

摘要 包括呼吸道病毒感染在内的呼吸道免疫挑战给社会带来了越来越大的负担。 呼吸道病毒感染，包括甲型流感病毒感染，可导致大脑功能改变；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。肺脏 和大脑通过几种信号机制进行双向交流，允许这些器官 相互影响。目前尚不清楚肺-脑通讯如何影响呼吸道病毒的进展。 感染，或在炎症反应进展过程中如何区分不同的沟通机制的优先顺序。 使用感染A型流感病毒株PR8的小鼠模型，这项建议探索了在 双向肺-脑轴。这一提议的首要目标是检验这样一个假设，即肺和 大脑在呼吸道感染过程中发挥双向作用，改变彼此的免疫状态。我的 初步数据显示，在感染PR8期间，中枢神经系统(CNS)的变化发生在 肺组织中炎性基因表达上调。影响这些中枢神经系统快速变化的信号机制 在神经元活动中，以及这种中枢神经系统反应在感染进展中的作用仍然未知。 肺神经内分泌细胞(PNECs)是在呼吸过程中启动免疫反应的感觉细胞。 炎症性挑战。这些细胞也是肺上皮中唯一直接由迷走神经支配的细胞。 很有胆量。尽管PNECs和迷走神经都具有已知的免疫功能，但PNECs信号转导到 呼吸道感染期间的中枢神经系统仍未得到研究。在目标1中，我将探索PNEC信号在 通过表征这些细胞在感染过程中发出的分子和迷走神经信号来识别感染。然后我会烧掉这些东西 利用依赖于cre的AAV递送机制在小鼠体内确定PR8感染前的细胞 它们的信号转导有助于外周或中枢神经系统对感染的反应。不管信令机制如何 启动中枢神经系统对PR8感染的快速反应，这种反应的最终结果尚不清楚。 神经元群可以编码免疫记忆，影响周围器官的免疫状态。在目标2中， 我将在整个PR8期间确定神经元活动如何影响小胶质细胞和外周免疫反应 感染发作。使用高通量成像和机器学习分析管道，我将绘制神经元 TRAP2：：TdTom小鼠对PR8感染的小胶质细胞反应。然后我将探索神经元活动的作用 通过使用TRAP2：：hM3Dq捕获并随后重新激活在PR8感染期间活跃的神经元群 老鼠。我将对中枢神经系统组织的小胶质细胞反应和外周免疫反应进行表征，以确定 PR8反应神经元群体的活动足以推动免疫结果。总而言之，这 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器官的影响 其他人的免疫状态在呼吸道感染的发作。

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.