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.