Neuroimmune interactions for laryngeal sensorimotor neuropathy in postviral influenza infection

摘要 喉部有丰富的神经支配，形成神经免疫小窝，构成 粘膜防御和生理中的双向相互作用。特发性髋关节感觉运动异常 喉，如急性声带麻痹和慢性过敏(慢性咳嗽、发作性喉痉挛) 归因于病毒病原学的上呼吸道感染。然而，病毒引起的一个因果联系 喉部病理生理学仍很薄弱。在本应用程序中，我将使用一个已建立的流感模型 病毒(IAV)感染检测喉粘膜重塑和定位传入/传出神经 幼稚和病毒感染组织中的电路/细胞。我将调查病毒感染的核心假设 喉将激活神经感觉细胞，重塑传入和传出神经，促进粘膜 发炎和过敏。我将利用小鼠遗传学的组合来检验这一假设， 组织清除和成像、单细胞转录和活体动物功能测试。我们预料到 这些激活的神经炎症信号是通过ASCL1+神经内分泌的独特群体检测到的 和Chat+细胞，为喉部神经病驱动神经感觉免疫回路。加在一起，这些 预计实验将确定神经感觉运动神经回路，并揭示神经免疫相互作用 协调病毒诱导的粘膜炎症后的修复途径。我们预计调查结果将指导 喉和声带炎性疾病创新治疗的新方向和领域 感觉运动性神经病。

ABSTRACT The larynx is richly innervated with nerves, forming neuroimmune niches that constitute the basis for bidirectional interactions in mucosal defense and physiology. Idiopathic sensorimotor abnormalities of the larynx, such as acute vocal fold paralysis and chronic hypersensitivity (chronic cough, episodic laryngospasm) are attributed to upper respiratory tract infections with a viral etiology. However, a causal link for viral-induced laryngeal pathophysiology remains tenuous. In this application, I will employ an established model of influenza A virus (IAV) infection to interrogate laryngeal mucosal remodeling and map afferent/efferent neural circuits/cells in naïve and virus infected tissues. I will investigate the central hypothesis that viral infection of the larynx will activate neurosensory cells, remodel both afferent and efferent nerves, contributing to mucosal inflammation and hypersensitivity. I will test this hypothesis utilizing a combination of mouse genetics, whole tissue clearing and imaging, single-cell transcriptomics and live animal functional testing. We anticipate that these activated neural inflammatory signals are detected via a unique population of ASCL1+ neuroendocrine and CHAT+ cells that drive a neurosensory-immune circuit for laryngeal neuropathy. Together, these experiments are expected to ascertain neural sensorimotor circuits and reveal neuroimmune interactions for coordinating repair pathways following viral-induced mucosal inflammation. We expect findings will guide the field in new directions for innovating treatments for laryngeal and vocal fold inflammatory diseases and sensorimotor neuropathies.