Dysregulation of fetal-derived RTMs mediates CMV-mediated sensorineural hearing loss 4816

Abstract Description Cytomegalovirus (CMV) is the most common congenital infection in the developed world and leading cause of non-genetic sensorineural hearing loss (SNHL) in children. We investigated the function of fetal-derived resident tissue macrophages (RTMs) in cochlear development and their role in CMV-mediated SNHL. Using genetic fate mapping, we uncovered temporal layering of fetal-derived RTMs from primitive and definitive hematopoiesis that naturally recede and expand concomitant with cochlear maturity. Transcriptomic analysis revealed fetal RTMs support cochlear tissue development (e.g. FGF and TGF-beta signaling). Embryonic depletion of fetal RTMs impaired cochlear tissue development and led to SNHL, revealing the essential role of fetal-derived RTMs in cochlear development. During CMV infection, fetal RTMs downregulated critical cochlear developmental pathway and upregulated inflammation-associated pathways. Both scRNAseq and fate-mapped analysis revealed infiltration of BM-derived macrophages and premature decline of primitive RTMs, indicating that CMV disrupted normal temporal layering of fetal-derived RTMs. Diphtheria-mediated depletion of primitive RTMs recapitulated CMV-mediated SNHL. Rapid replacement by BM macrophages, phenotypically similar to primitive RTMs, failed to support tissue development and led to SNHL. These data reveal primitive RTMs and layered RTM establishment regulate cochlear development as a novel pathogenic mechanism underlying CMV-mediated SNHL. Funding Sources Supported by T32AI138954; F31DC021388; R01DC022156 Topic Categories Innate Immune Responses and Host Defense: Cellular Mechanisms (INC)