Rift Valley Fever Virus Infection Causes Acute Encephalitis in the Ferret

Abstract

Rift Valley fever virus (RVFV) is a pathogen of both humans and livestock in Africa and the Middle East. Severe human disease is associated with hepatitis and/or encephalitis. Current pathogenesis studies rely on rodents and nonhuman primates, which have advantages and disadvantages. We evaluated disease progression in Mustela putorius furo (the ferret) following intradermal (i.d.) or intranasal (i.n.) infection. Infected ferrets developed hyperpyrexia, weight loss, lymphopenia, and hypoalbuminemia. Three of four ferrets inoculated intranasally with RVFV developed central nervous system (CNS) disease that manifested as seizure, ataxia, and/or hind limb weakness at 8 to 11 days postinfection (dpi). Animals with clinical CNS disease had transient viral RNAemia, high viral RNA loads in the brain, and histopathological evidence of encephalitis. The ferret model will facilitate our understanding of how RVFV accesses the CNS and has utility for the evaluation of vaccines and/or therapeutics in preventing RVFV CNS disease. IMPORTANCE Animal models of viral disease are very important for understanding how viruses make people sick and for testing out drugs and vaccines to see if they can prevent disease. In this study, we identify the ferret as a model of encephalitis caused by Rift Valley fever virus (RVFV). This novel model will allow researchers to evaluate ways to prevent RVFV encephalitis.

Acute Rift Valley fever virus infection induces inflammatory cytokines and cell death in ex vivo rat brain slice culture

“…Previous literature suggest that RVFV readily infects neurons, microglia, and astrocytes in vitro and in vivo, resulting in a highly inflammatory environment including cell death and cytokine dysregulation [6,7,10,12,29,36]. In particular, GRO/KC, IL-1β and MCP-1 are produced at high levels at end-stage disease in the brain of rats infected with RVFV by inhalational exposure [12].…”

“…Our lab and others have developed animal models to study RVFV encephalitis in laboratory mice, rats, and ferrets [6][7][8][9]. In rats, inhalational exposure to pathogenic RVFV (strain ZH501) results in consistent neurologic symptoms and lethality between 7-10 days [8].…”

Nonrespiratory sites of influenza‐associated disease: mechanisms and experimental systems for continued study

“…Ferrets develop fevers in response to influenza viral infections [41], perhaps providing an opportunity to study extrapulmonary influenza disease associated with raised temperatures. Virus-associated seizures, which are known to occur during CNS viral infections in ferrets [44,182,183], are one such example of a hyperthermia induced phenotype difficult to model in mice. In particular, ferrets are an appropriate model for the impact of age on the response to influenza infection [184], an issue highlighted in this review by pediatric patients' vulnerability to neurological effects of influenza and older populations greater risk for cardiac and muscular manifestations of disease.…”

The dissemination of Rift Valley fever virus to the eye and sensory neurons of zebrafish larvae is stat1 dependent

“…(52) Our finding is contradictory to earlier studies in RVFV-infected rats and ferrets, where acute encephalitis and infection of the brain was observed. (53, 54) However, it should be noted that in those studies the animals were infected through aerosol exposure, rather than via intravenous or subcutaneous administration, which alters the pathogenesis of RVFV. (55) A similar approach, i.e., RVFV inoculation through the olfactory system, could be used in zebrafish adults and eventually, in larvae.…”