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Published on: January 9, 2019
Cytomegalovirus-induced sensorineural hearing loss with persistent cochlear inflammation in neonatal mice
Scott J Schachtele1, Manohar B Mutnal, Mark R Schleiss
1Center for Infectious Diseases and Microbiology Translational Research, Department of Medicine, University of Minnesota, Minneapolis, MN, USA.
Abstract:
Congenital cytomegalovirus (CMV) infection is the leading cause of sensorineural hearing loss (SNHL) in children. During murine (M)CMV-induced encephalitis, the immune response is important for both the control of viral dissemination and the clearance of virus from the brain. While the importance of CMV-induced SNHL has been described, the mechanisms surrounding its pathogenesis and the role of inflammatory responses remain unclear. This study presents a neonatal mouse model of profound SNHL in which MCMV preferentially infected both cochlear perilymphatic epithelial cells and spiral ganglion neurons. Interestingly, MCMV infection induced cochlear hair cell death by 21 days post-infection, despite a clear lack of direct infection of hair cells and the complete clearance of the virus from the cochlea by 14 dpi. Flow cytometric, immunohistochemical, and quantitative PCR analysis of MCMV-infected cochlea revealed a robust and chronic inflammatory response, including a prolonged increase in reactive oxygen species production by infiltrating macrophages. These data support a pivotal role for inflammation during MCMV-induced SNHL.
Insights
Congenital cytomegalovirus (CMV) infection causes hearing loss in children. In mice, CMV infection of the cochlea triggers inflammation and hair cell death, even after the virus is cleared, highlighting inflammation's role in CMV-induced hearing loss.
Area of Science:
- Virology
- Immunology
- Otolaryngology
Background:
- Congenital cytomegalovirus (CMV) is a primary cause of sensorineural hearing loss (SNHL) in children.
- The pathogenesis of CMV-induced SNHL and the role of inflammatory responses remain incompletely understood.
Purpose of the Study:
- To investigate the mechanisms of SNHL in a neonatal mouse model of murine CMV (MCMV) infection.
- To elucidate the role of inflammatory responses in MCMV-induced cochlear damage and hearing loss.
Main Methods:
- Development of a neonatal mouse model for MCMV-induced SNHL.
- Analysis of MCMV infection in cochlear cells, including perilymphatic epithelial cells and spiral ganglion neurons.
- Assessment of cochlear hair cell integrity and viral clearance.
- Flow cytometry, immunohistochemistry, and quantitative PCR to analyze inflammatory markers, including reactive oxygen species (ROS) and macrophage infiltration.
Main Results:
- MCMV preferentially infected cochlear perilymphatic epithelial cells and spiral ganglion neurons, leading to profound SNHL.
- Cochlear hair cell death occurred by 21 days post-infection, independent of direct hair cell infection and after viral clearance.
- A robust, chronic inflammatory response was observed in the infected cochlea, characterized by prolonged ROS production by macrophages.
Conclusions:
- Inflammation plays a critical role in the pathogenesis of MCMV-induced SNHL.
- The study provides a valuable mouse model for investigating CMV-induced hearing loss and potential therapeutic interventions.
