Neuroimmune interactions for laryngeal sensorimotor neuropathy in postviral influenza infection

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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.