Balance Dysfunction Induced by Lassa Virus Infection

PROJECT SUMMARY/ABSTRACT Lassa virus (LASV) infection causes Lassa Fever (LF), a hemorrhagic fever endemic to West Africa. Up to 30% of LASV infection survivors develop sudden onset hearing loss after clearing the initial acute disease, and in some cases also develop dizziness and imbalance, similar to labyrinthitis or vestibular neuritis or idiopathic sudden sensorineural hearing loss, all of which are diseases with unknown etiology seen worldwide. Viral infection is speculated to play a role. However, the responsible virus nor the molecular mechanism leading to dizziness is unknown. The aim of this project is to investigate how the vestibular processing is affected leading to dizziness or balance problems after a viral infection using the LF model mice. Our short-term goal for this proposal is 1) to characterize the vestibular behavioral and cellular changes in LF model mice, and 2) to determine the most effective treatment/prevention modality for the balance dysfunction in LF model mice. Our long-term goal is to use this general model to determine the mechanisms leading to balance dysfunction after a viral infection, and to develop effective prevention and treatment methods in humans. Specific Aim 1: Characterize vestibular histopathology of LF model mice as a function of time lapse after infection. We will determine the onset, degree, location of the damage at timepoints starting at 2 days to 90 days post-infection in association with vestibular behavior changes in rotarod, balance beam in Biosafety Level-4 environment. Specific Aim 2: Characterize balance dysfunction in the LF surrogate model ML29 infected mice. We will use the LF surrogate model ML29 infected mice to perform in-depth vestibular behavioral tests in the Biosafety Level-2 environment. We will contrast vestibular ocular reflex tests with rotarod test, balance beam test and gross vestibular behavioral tests in mice infected with LASV and ML29, and determine the histological changes in the inner ear associated with vestibular dysfunction in ML29 infected mice. Histopathology analysis will focus on changes in spatial and planar anatomical changes using 3-D anatomical mapping of the inner ear vestibular organs using tissue clearing in addition to thin sections. Specific Aim 3: Determine the modality and timing of treatment to improve balance performance outcome. We hypothesize that damage to the inner ear after infection with LASV causes mechanical damage in early timepoints whereas immune mediated damage is triggered in association with the mechanical damage at later timepoints. We will determine the difference in response after systemic or intratympanic administration of immunosuppressive agents or hyperbaric oxygen treatment at early and later timepoints after LASV infection. Our project is innovative because we will assess novel animal models of viral infection induced balance dysfunction that likely shares the same pathophysiology with labyrinthitis/vestibular neuritis in humans.