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

呼吸道病毒感染发作时的肺脑通讯。

• 批准号: 10750154
• 负责人: Sarah Katherine Monroe
• 金额: $ 4.28万
• 依托单位: DUKE UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2023
• 资助国家: 美国
• 起止时间: 2023-08-01 至 2026-07-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10750154
• 关键词: 3-Dimensional; Ablation; Attenuated; Automobile Driving; Brain; COVID-19 pandemic; Cell Count; Cells; Central Nervous System; Central Nervous System Infections; Communication; Computer software; Data; Designer Drugs; Epithelial Cells; Epithelium; Face; Focal Infection; Gene Expression; Genes; Genetic; Genetic Recombination; Goals; Health; Hippocampus; Image; Immune; Immune response; Immune signaling; Immunologic Memory; Impairment; Infection; Inflammation; Inflammatory; Inflammatory Response; Influenza A virus; Invaded; Knowledge; Label; Link; Lung; Lung infections; Machine Learning; Maps; Measures; Microglia; Modeling; Molecular; Morphology; Mus; Neuroendocrine Cell; Neuroimmune; Neurons; Neuropeptides; Organ; Outcome; Peripheral; Phagocytes; Population; Proteomics; Recovery; Respiratory Tract Infections; Role; Sensory; Signal Pathway; Signal Transduction; Societies; Structure of parenchyma of lung; Testing; Tissues; Up-Regulation; Vagus nerve structure; Viral Respiratory Tract Infection; Virus; Virus Diseases; analysis pipeline; brain health; brain tissue; cognitive function; cytokine; designer receptors exclusively activated by designer drugs; experience; immune cell infiltrate; immune function; indexing; influenza infection; lung health; mouse model; nerve supply; neural; neurotransmission; respiratory; respiratory challenge; response

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.

抽象的 社会面临着呼吸道免疫挑战（包括呼吸道病毒感染）带来的日益沉重的负担。 呼吸道病毒感染，包括甲型流感病毒，会导致大脑功能发生变化；理解 肺和大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 大脑通过多种信号机制进行双向通信，使这些器官 来互相影响。目前尚不清楚肺脑通讯如何影响呼吸道病毒的进展 感染，或随着炎症反应的进展，不同的通讯机制如何优先排序。 该提案利用感染甲型流感 PR8 株的小鼠模型，探讨了免疫信号传导 双向肺脑轴。该提案的总体目标是检验肺和 大脑在呼吸道感染期间发挥双向影响，改变彼此的免疫状态。我的 初步数据显示，在PR8感染期间，中枢神经系统（CNS）的变化发生在PR8感染之前。 肺组织炎症基因上调。影响这些中枢神经系统快速变化的信号机制 神经元活动的影响，以及这种中枢神经系统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 炎症挑战。这些细胞也是肺上皮中唯一受迷走神经直接支配的细胞 神经。尽管 PNEC 和迷走神经的免疫功能已知，但 PNEC 信号传导的作用 呼吸道感染期间的中枢神经系统尚未得到研究。在目标 1 中，我将探讨 PNEC 信号传导在 通过表征感染过程中这些细胞的分子和迷走神经信号传导来识别感染。然后我会消除这些 在 PR8 感染之前使用 cre 依赖性 AAV 递送机制在钙化小鼠中检测细胞，以确定是否 它们的信号传导有助于外周或中枢神经系统对感染的反应。与信号机制无关 启动中枢神经系统对 PR8 感染的快速反应，但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， 我将确定整个 PR8 期间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流程，我将绘制神经元图 TRAP2::TdTom 小鼠中小胶质细胞对 PR8 感染的反应。然后我将探讨神经元活动的作用 通过使用 TRAP2::hM3Dq 捕获并随后重新激活 PR8 感染期间活跃的神经元群 老鼠。我将描述中枢神经系统组织中的小胶质细胞反应和外周免疫反应，以确定是否 PR8 反应性神经元群的活性足以驱动免疫结果。总而言之，这 该提案将探讨肺和大脑健康之间的联系，重点关注这些器官对每个器官的影响 呼吸道感染发作时他人的免疫状态。