Altered epithelial function in the stria vascularis and hearing loss in a mouse model of congenital cytomegalovirus infection associated hearing loss

Abstract

Abstract Congenital Human Cytomegalovirus (HCMV) infection is a leading cause of sensorineural hearing loss (SNHL) in children. The mechanism of HCMV damage to the developing auditory system that leads to SNHL is not understood and effective treatments are lacking. We developed a murine model of HCMV infection that results in neurodevelopmental abnormalities and SNHL, thus providing a useful model to study the mechanisms of SNHL associated with cCMV infection. We have shown that MCMV induces expression of proinflammatory molecules and immune cell activation in the cochlea associated with histopathologic changes and SNHL. The stria vascularis (SV) plays a critical role in hearing by; (1) maintaining an epithelial barrier needed for generation of the high electrical potential of endocochlear fluid surrounding the hair cells; (2) expression of a system of ion channels that create a high K +concentration in the endocochlear fluid; and (3) generation of a blood labyrinth barrier (BLB) that surrounds the vasculature in the SV and functions like the blood brain barrier. Utilizing several assays, our studies showed that MCMV infection altered each of these functions. The transcription and protein expression in the SV required for tight junctions in the epithelial barrier and ion channels were decreased early after infection and in SV from infected mice with SNHL compared to those without SNHL. In addition, the resident macrophages that contribute to the BLB had altered phenotypes. Functionally, penetration of a cell-impermeable tracer into the SV could be demonstrated in MCMV infected mice. In all, our data show that MCMV dysregulates expression of key proteins in the SV that in turn impact the capacity of the SV to maintain the cochlea’s unique environment.