Friday, May 16, 2025
5/16/2025
Mechanism of Lassa virus-associated sensorineural hearing loss - PROJECT SUMMARY/ABSTRACT Lassa virus (LASV), the causative agent of Lassa fever (LF), infects thousands of individuals annually in West Africa and has a case fatality rate of up to 69% in outbreak scenarios. Survivors of LASV infection are at high risk of developing bilateral, permanent sensorineural hearing loss (SNHL). Though the prevalence of SNHL following LASV infection is 10-300 times greater than other common viral causes of hearing loss, the mechanism driving this debilitating sequela is largely unknown. Prior research published by our laboratory implementing a signal transducer and activator of transcription 1 knock-out (STAT1-/-) mouse model of LASV-associated SNHL indicates that viral infection alone is not capable of inducing hearing loss. Alternatively, our results show that immune injury mediated by CD4+ T cells is pivotal to SNHL development. However, how these CD4+ T cells induce hearing degeneration remains to be determined. Currently, it is unknown whether the immune response is auto-immune in nature, resulting from cross-recognition of inner ear proteins with viral antigens (i.e. molecular mimicry), or a response to persistently infected inner ear cells. Additionally, it is unknown if the role CD4+ T cells play in the antibody response to infection is responsible for SNHL development. The contribution of immune- mediated injury to the development of SNHL has critical implications for vaccine design. If the damage leading to SNHL results from the humoral response to viral antigen or auto-immune recognition of inner ear proteins driven by their similarity to viral antigens, then vaccines implementing these antigens may induce hearing loss in vaccine recipients. As a result, the objective of this application is to identify the role of antibodies and the role and antigenic specificity of CD4+ T cells involved in SNHL development, allowing for assessment of the risks associated with vaccination against LASV. To accomplish this, CD4+ T cells derived from mice vaccinated with recombinant vesicular stomatitis virus (rVSV) expressing the LASV glycoprotein (GPC) or nucleoprotein (NP) will be adoptively transferred into infected or uninfected STAT1-/- mice. Additionally, LASV immune sera will be passively transferred into infected or uninfected STAT1-/- mice. These studies will allow for evaluation of our central hypothesis, that immune-mediated damage driven by CD4+ T cells recognizing autoantigen in the cochlear nerve is responsible for the development of SNHL following LASV infection. Using our STAT1-/- murine model of LASV-associated SNHL, we propose to evaluate this hypothesis by pursuing two specific aims. Specific Aim 1 will investigate the ability of antigen primed CD4+ T cells to induce SNHL. Specific Aim 2 will investigate the ability of polyclonal anti-LASV antibodies to induce SNHL. These studies will comprehensively evaluate the role of the T cell-mediated and humoral immune responses in the immunopathology related to SNHL. Findings from the proposed research will be critical to achieving our long-term goal of developing safe vaccines against LASV and identifying therapeutic targets to prevent SNHL.
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