ANIMAL MODELS FOR BEHAVIORAL CHANGES OR HEARING LOSS UPON ACUTE VIRUS INFECTIONS

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Sequelae are defined as a condition resultant of disease, typically a chronic complication of an acute illness. Neurological sequelae are those complications involving the brain and central nervous system and can include intellectual disability, seizures, emotional instability, vision loss, and hearing loss. Although many viral infections may lead to sequelae, two genera of single stranded RNA viruses are of high importance to study as models of neurological sequelae; arenaviruses and alphaviruses. Both of these viruses are important human pathogens and the cause of the long-term neurological damage, the related pathology and the mechanisms associated with sequelae have not been identified. Sensorineural hearing loss is detected in 25% of Lassa fever patients and up to 90% of encephalitic alphavirus infections result in severe behavioral changes. Well-established murine models are available to study each of these viruses’ initial infection, including the wild-type C57BL/6 model of acute infection with the alphavirus Venezuelan equine encephalitis virus (VEEV) and the Stat1 knockout (Stat1-/-) murine infection model with the Old World arenavirus Lassa virus. Here, I have adapted these models to study the sequelae of humans in murine models. I have replicated an array of behavioral changes resultant of alphavirus infection using a low-dose intranasal infection of TC-83, an attenuated strain of VEEV, where 30% of animals develop signs of diseases and 100% of those animals develop significant changes not seen in asymptomatic or mock animals. These animals also had increased glial fibrillary acidic protein (GFAP) expression, indicating increased astrocyte activation, in the dentate gyrus and thalamus. In the Stat1-/- model of LASV infection, I found that 100% of survivors developed hearing loss post-infection, which correlated with severe damage to the cochlear nerve and CD3 positive staining in the spiral ganglion, organ of corti, and scala tympani. This same damage was not observed in IFNabgR-/- mice although those mice developed systemic infection with higher virus loads in most tissues. This indicates that the damage to the cochlear nerve is at least partially driven through immunological mechanisms.

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Lassa virus, alphavirus, neurological sequelae
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