Hearing loss associated with congenital human cytomegalovirus (HCMV) infection, a relatively frequent perinatal infection, accounts for nearly 25% of all causes of hearing loss in infants and children in the US. The mechanisms of disease caused by infection of the inner ear by this large herpesvirus are unknown, primarily because of hurdles inherent in the investigation of the inner ear in humans. We have developed an informative murine model of hearing loss in which newborn mice are infected peripherally and not intracranially with the closely related murine CMV. In this model, about 30-50% of infected mice develop sensorineural hearing loss and a significant number of mice with hearing loss exhibit progression in hearing loss, a clinically important feature of hearing loss in infants with HCMV associated hearing loss. Our findings strongly argue that virus-induced inflammation and not direct viral cytopathology is responsible for hearing loss and progressive hearing loss in this model. Our studies will explore this hypothesis by defining mechanisms of damage to the developing auditory system and hearing loss in animals associated with CMV-induced inflammation of the inner ear. Results from these studies will guide investigation into mechanisms of hearing loss in infants and children with HCMV associated hearing loss and identify therapeutic approaches that can be translated into treatment and prevention of hearing loss in CMV infected infants.

Public Health Relevance

Congenital infection with human cytomegalovirus (HCMV) occurs in about 1/200 live births and 10% of these infants develop hearing loss. We have developed a mouse model of this human infection in which infected mice develop hearing loss with characteristics similar to humans. Findings from this model have suggested that virus-induced inflammation and not direct damage to the inner ear by the virus infection is responsible for hearing loss, new insights into mechanisms of disease provided by this model could point to new therapeutic approaches to limit hearing loss in infants infected with HCMV.

Agency
National Institute of Health (NIH)
Institute
National Institute on Deafness and Other Communication Disorders (NIDCD)
Type
Research Project (R01)
Project #
5R01DC015980-04
Application #
9986723
Study Section
Special Emphasis Panel (ZRG1)
Program Officer
Watson, Bracie
Project Start
2017-09-01
Project End
2022-08-31
Budget Start
2020-09-01
Budget End
2021-08-31
Support Year
4
Fiscal Year
2020
Total Cost
Indirect Cost
Name
University of Alabama Birmingham
Department
Pediatrics
Type
Schools of Medicine
DUNS #
063690705
City
Birmingham
State
AL
Country
United States
Zip Code
35294
Brizi?, Ilija; Hiršl, Lea; Britt, William J et al. (2018) Immune responses to congenital cytomegalovirus infection. Microbes Infect 20:543-551