The role of resident tissue macrophages in cytomegalovirus-associated sensorineural hearing loss

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ABSTRACT The cochlea is a delicate and structurally complex part of the inner ear peripheral auditory system that is developmentally sensitive to early life infection and inflammation. Recent studies have shown fetal-derived resident tissue macrophages (RTMs) are distributed across key areas of the cochlea, and are required for proper cochlea development. Our preliminary data and published data identify cochlea RTMs as sensitive responders to cytomegalovirus (CMV) and are implicated in cochlear damage and sensorineural hearing loss (SNHL). While fetal-derived RTMs have been identified in cochlea, their precise origin and function is unknown. RTMs are heterogeneous and include 1) primitive macrophages derived from yolk sac hematopoiesis and 2) definitive macrophages derived from fetal liver hematopoiesis. We will investigate relative contribution of primitive and definitive RTMs in normal cochlea development, their spatial distribution within the cochlea, and examine how these interactions go awry in response to CMV infection to drive dysfunction. Our investigation offers a unique opportunity to understand both how tissue environment can influence phenotype and how spatial seeding of RTMs influences normal tissue development and architecture. Our working hypothesis is that CMV infection drives abnormal cochlea RTM development, thereby impairing cochlea tissue development and causing SNHL. We will investigate this hypothesis by completing our following aims: Aim 1: Determine the origin, localization, and contribution of specific RTM subsets within the cochlea Aim 2: Understand the role of specific RTM subsets in cochlear tissue development and function Aim 3: Determine the impact of CMV on the establishment and persistence of fetal-derived RTMs The objective of this proposed work is to elucidate new level of mechanistic insight into how RTMs contribute to normal function of cochlea tissue and cochlear immunity, and within the context of disease and disorders, how RTMs mediate CMV-associated SNHL. This proposal will shed light on pathological mechanisms of SNHL on RTM and cochlea tissue. Collectively the proposed work will, for the first time, give us insight into the link between fetal-derived resident cells and tissue architecture, and will provide insight for RTMs as a potential novel therapeutic target for SNHL treatment.