Molecular etiology of virus-induced sensorineural hearing loss

PROJECT ABSTRACT Viral infection is a common cause of sensorineural hearing loss (SNHL). However, the underlying mechanism is poorly understood. For most viruses, it is unclear whether SNHL is caused by direct viral infection of inner ear tissue or by a secondary effect through an immune response, or a combination of both. Antiviral drugs and steroids only improve the outcome for a small group of patients. It is therefore imperative to understand the molecular etiology of virus-induced SNHL for the development of effective preventions and treatments. The research proposes a systemic evaluation of viral effects on the inner ear using mumps virus (MuV), a human virus that causes SNHL after birth (acquired SNHL), and murine cytomegalovirus (mCMV) to understand human CMV disease that causes SNHL during embryonic development (congenital SNHL). There is no small animal model to assess SNHL caused by MuV. In Aim1, it is proposed to establish novel in vivo mouse models to assess how mCMV and MuV infections affect inner ear cells. Infection will be done locally and controlled via the posterior semicircular canal. The onset and extent of hearing loss will be measured by auditory brainstem response and distortion product otoacoustic emissions. Histochemistry will quantify apoptotic cells, virus-infected cells, and immune cells in defined anatomical locations of the cochlea from apex to base. Because the model is expected to be highly controllable, it will be optimized so that the detrimental mechanisms of different viruses can be compared to advance the mechanistic understanding of virus-induced SNHL. Aim2 focuses on understanding the etiology of the tissue damage -direct viral infection or immune response- in mCMV- and MuV- administrated cochleae, and to analyze the mechanisms at the cellular and molecular level. Susceptible cell subtypes will be quantified in P2 and P21 mice injected with mCMV and MuV before and after the onset of hearing loss by using known and recently identified markers. These include new pericochlear cell subtypes in the neonatal cochlea that were recently reported by the principal investigator (PI), as well as the new subtypes of type I spiral ganglion cells. The expression of a ganglioside called GM2, a MuV receptor which the PI identified in a previous study, and various viral host factors will be also quantified in each cochlear cell subtype to understand their correlation with cellular damage. Further, the types and numbers of infiltrating immune cells post PSC injection of mCMV and MuV in P2 and P21 mice will be assessed with flow cytometric analysis with cell type-specific markers. Together, completion of these aims will provide essential details of the mechanism of SNHL caused by mCMV and MuV, and will establish a protocol that can be applied to other hearing loss-causing viruses such as Lassa virus, which is not suitable for animal model development because of its high biosafety level. The PI envisions this project as the first step of her future research journey as a clinician-scientist with a focus on prevention and treatment of viral-induced SNHL.