Dysregulation of fetal-derived cochlear resident tissue macrophages mediates CMV-associated sensorineural hearing loss

Abstract Cytomegalovirus (CMV) is the most common congenital viral infection in developed world and leading cause of non-genetic sensorineural hearing loss (SNHL) children. Congenital CMV causes progressive SNHL long after acute has resolved, suggesting a lasting effect on developing host immune response cochlea. Using fate-mapping models, we investigated contribution fetal-derived resident tissue macrophages (RTMs) to normal cochlear development function, their role mediating CMV-associated SNHL. We uncovered dual RTMs (F4/80 hiCD11b lo) from yolk sac (YS) fetal liver (FL) hematopoiesis at birth. YS-derived naturally recede postnatally cochlea development, but remain key tissues, such as spiral ligament stria vascularis, through adulthood. Depletion by anti-CSF1R blocking Ab led impairments architecture. Similarly, embryonic deletion induced CSF1R leads high frequencies. During infection, expand become transcriptionally dysregulated developmental programs, including remodeling, chemorepulsion, otic vesicle morphogenesis, FGF signaling. Importantly, analysis CSF1R-Cre labeling suggests retract RTM expansion caused infiltration BM-derived macrophages. Ongoing work examines spatial distribution RTMs, transcriptional differences between YS, FL, CMV, how replacement with affects function CMV. Supported grants NIAID (T32 5T32AI138945) University Utah molecular medicine immunology, inflammation infectious disease (3i) initiative