The contribution of fetal-derived tissue resident macrophages to cytomegalovirus-associated sensorineural hearing loss

Abstract

Abstract Cytomegalovirus (CMV) is the most common congenital viral infection in the developed world and the leading cause of non-genetic sensorineural hearing loss (SNHL) in children. Congenital CMV causes progressive SNHL long after acute infection has resolved, suggesting a lasting effect on the developing host immune response within the cochlea and surrounding temporal bone marrow (TB). Using fate-mapping models, we have investigated the contribution of fetal-derived tissue resident macrophages (TRMs) to normal cochlear development and function, and their role in mediating CMV-associated SNHL. Our analysis defined two distinct myeloid population within the inner ear: 1) classical tissue resident macrophages (F4/80hiCD11blo) that highly express CD64 and are found exclusively in cochlear tissue; and 2) transitional monocytes (F4/80midCD11bhi) that express both CD64 and Ly6C and are found in cochlea and TB. Fate mapping of these populations uncovered dual contribution of fetal-derived cochlear TRMs from yolk sac (YS) and fetal liver (FL) hematopoiesis. Transitional monocytes increase during acute CMV infection, acting as drivers of expanded lymphoid populations after CMV resolves. Importantly, analysis of Flt3-Cre labeling within myeloid populations suggests that TRMs are replaced by BM-derived populations at later postnatal stages following CMV infection, coinciding with SNHL. Ongoing work examines spatial distribution of distinct fetal-derived TRMs along cochlear architecture, defining transcriptional regulation differences between YS-, FL-, and adult-derived TRMs in response to CMV, and examining how replacement of fetal-derived TRMs with adult-derived TRMs affects tissue function and response to infection. Supported by grants from University of Utah Molecular Medicine and Immunology, Inflammation and Infectious Disease (3i) Initiative and NIAID (T32 5T32AI138945)