Murine CMV-Induced Hearing Loss Is Associated with Inner Ear Inflammation and Loss of Spiral Ganglia Neurons

Abstract

Congenital human cytomegalovirus (HCMV) occurs in 0.5–1% of live births and approximately 10% of infected infants develop hearing loss. The mechanism(s) of hearing loss remain unknown. We developed a murine model of CMV induced hearing loss in which murine cytomegalovirus (MCMV) infection of newborn mice leads to hematogenous spread of virus to the inner ear, induction of inflammatory responses, and hearing loss. Characteristics of the hearing loss described in infants with congenital HCMV infection were observed including, delayed onset, progressive hearing loss, and unilateral hearing loss in this model and, these characteristics were viral inoculum dependent. Viral antigens were present in the inner ear as were CD3+ mononuclear cells in the spiral ganglion and stria vascularis. Spiral ganglion neuron density was decreased after infection, thus providing a mechanism for hearing loss. The lack of significant inner ear histopathology and persistence of inflammation in cochlea of mice with hearing loss raised the possibility that inflammation was a major component of the mechanism(s) of hearing loss in MCMV infected mice.

Cytomegalovirus (CMV) Infection Causes Degeneration of Cochlear Vasculature and Hearing Loss in a Mouse Model

“…However, we are still uncertain about how the virus infiltrates the inner ear. It has recently been reported in a mouse model that mCMV is found in the bone marrow of the inner ear (Bradford et al 2015). We can confirm that observation; we have detected a significant viral signal in the bone marrow of the cochlear apex at 1-3 days post-inoculation.…”

“…An important question is whether such losses, as measured in our model by ABR and DPOAE recording, or with audiometric tests in human CMV infection, relate solely to EP changes after strial dysfunction, or whether hair cells or cochlear neural elements are directly damaged by viral insult. There is much evidence to suggest that the organ of Corti is not the initial target of the virus (Li et al 2008;Schachtele et al 2011;Wang et al 2013;Bradford et al 2015;Li et al 2015). It is important to note that the apical vascular damage in the present study is not reflected in predominantly low frequency ABR or DPAOE threshold changes (Fig.…”

Congenital hearing loss

“…43, 44 In another murine model of CMV infection, hearing loss was associated with a loss in spiral ganglion neurons following experimental challenge. 45 In addition to the direct cytolytic effect of viral infection, there is also evidence for immune injury, mediated by both the host immune response as well as the expression of viral genes encoding pro-inflammatory chemokines. 46 The virulence of the virus and the immune responses of the mother, fetus and placenta have a crucial role in the outcome.…”

Activation of TRAIL‐DR5 pathway promotes sensorineural degeneration in the inner ear

“…For example, microbial infections of the middle ear, such as with Streptococcus pneumoniae (Dodge et al ., 1984), Haemophilus influenzae type B (Feldman et al ., 1982), or cytomegalovirus (Bradford et al . 2015), can spread to the inner ear and induce inflammation resulting in sensorineural hearing loss. Importantly, such hearing loss can be prevented with anti‐inflammatory medications (Brouwer et al ., 2013).…”