Animal Model of Sensorineural Hearing Loss Associated with Lassa Virus Infection

Abstract

Approximately one-third of Lassa virus (LASV)-infected patients develop sensorineural hearing loss (SNHL) in the late stages of acute disease or in early convalescence. With 500,000 annual cases of Lassa fever (LF), LASV is a major cause of hearing loss in regions of West Africa where LF is endemic. To date, no animal models exist that depict the human pathology of LF with associated hearing loss. Here, we aimed to develop an animal model to study LASV-induced hearing loss using human isolates from a 2012 Sierra Leone outbreak. We have recently established a murine model for LF that closely mimics many features of human disease. In this model, LASV isolated from a lethal human case was highly virulent, while the virus isolated from a nonlethal case elicited mostly mild disease with moderate mortality. More importantly, both viruses were able to induce SNHL in surviving animals. However, utilization of the nonlethal, human LASV isolate allowed us to consistently produce large numbers of survivors with hearing loss. Surviving mice developed permanent hearing loss associated with mild damage to the cochlear hair cells and, strikingly, significant degeneration of the spiral ganglion cells of the auditory nerve. Therefore, the pathological changes in the inner ear of the mice with SNHL supported the phenotypic loss of hearing and provided further insights into the mechanistic cause of LF-associated hearing loss. IMPORTANCESensorineural hearing loss is a major complication for LF survivors. The development of a small-animal model of LASV infection that replicates hearing loss and the clinical and pathological features of LF will significantly increase knowledge of pathogenesis and vaccine studies. In addition, such a model will permit detailed characterization of the hearing loss mechanism and allow for the development of appropriate diagnostic approaches and medical care for LF patients with hearing impairment.

Arenaviridae exoribonuclease presents genomic RNA edition capacity

“…Indeed, LASV is responsible for several hundred thousand infections per year alone [14]. It is a common endemic infection in West Africa (Sierra Leone, Guinea, Liberia, Nigeria) responsible for hearing loss, tremors and encephalitis [13,15]. Moreover, this endemic infection frequently spikes a high number of Lassa fever cases associated with significant mortality and high morbidity.…”

Imported Case of Lassa Fever in Sweden With Encephalopathy and Sensorineural Hearing Deficit

“…However, spontaneous improvement of the neurological symptoms including speech and bradyphrenia occurred, and the most pronounced symptom when the diagnosis was made was the loss of hearing. Auditory nerve damage may develop even during ribavirin treatment [14], supporting an immunological mechanism [15], and the decision to refrain from antiviral therapy was made after a detailed discussion.…”

Differential Immune Responses to Hemorrhagic Fever-Causing Arenaviruses

“…Studies using a rodent model of LASV-induced hearing loss have provided further evidence that hearing loss may be caused by a cell-mediated immune response rather than through direct viral damage [105]. STAT1 knockout mice infected by clinical LASV isolates develop sensorineural hearing loss, though IFNαβ/γ receptor knockout mice do not.…”

“…STAT1 knockout mice infected by clinical LASV isolates develop sensorineural hearing loss, though IFNαβ/γ receptor knockout mice do not. Interestingly, while LASV antigen can be detected in the inner ears of both types of mice, tissue damage was only observed in the STAT1 knockout mice concomitant with profound CD3-positive lymphocytic infiltration [105]. It would be interesting to determine if depletion of T cells could prevent hearing loss in this model.…”