Dysregulation of fetal-derived cochlear resident tissue macrophage mediate CMV-associated sensorineural hearing loss

Abstract

Abstract Cytomegalovirus (CMV) is the most common congenital viral infection in the developed world and leading cause of non-genetic sensorineural hearing loss (SNHL) in children. Here we investigated the role of fetal-derived resident tissue macrophages (RTMs) in normal cochlear development and their role in CMV-associated SNHL. Using genetic fate mapping, we uncovered dual sources of fetal-derived RTMs from yolk sac (YS) and fetal liver (FL) hematopoiesis. YS-derived RTMs naturally recede after cochlea maturity while FL-derived RTMs expand, revealing a temporal layering of RTMs. Additionally YS-derived and FL-derived RTMs demonstrate spatial specificity, seeding distinct cochlear tissues. Both anti-CSF1R depletion of fetal-RTMs and embryonic genetic deletion of YS-derived RTMs by CSF1R-flox lead to SNHL and impaired cochlear tissue development, revealing the requirement for fetal RTMs in normal cochlear development. During CMV infection, scRNAseq and fate-mapping analysis revealed an infiltration of bone marrow-derived macrophages at the expense of yolk-sac derived RTMs, indicating that CMV infection disrupted the normal temporal layering of fetal-derived RTMs in the cochlea. Fetal-derived RTMs also upregulated inflammation-associated pathways and downregulated pathways critical for inner ear development, such as FGF and TGFb signaling. Together these data reveal perturbation of developing RTMs that regulate normal cochlear development as a mechanism underlying CMV-mediated SNHL.