Understanding the neuropathogenesis of Rift Valley Fever using in vitro and in vivo models

Rift Valley Fever Virus (RFVF) is a mosquito-borne pathogen found primarily within Africa that is capable of causing both human and animal illness. In humans, RVFV can cause different clinical diseases, with encephalitis being one of the more severe outcomes. In order to study the neuropathogenic mechanisms of RVFV, our laboratory developed the Lewis rat model. When exposed to RVFV via the aerosol route, Lewis rats develop a uniformly lethal encephalitic disease with neurological symptoms. The goal of this research study is to compare in vitro brain cell culture systems to the in vivo brain environment of rats infected with RVFV, further define the systemic (serum) and regional (CNS) cytokine dysregulation that occurs in infected rats, and explore the neuropathogenesis using an animal model. The results presented here demonstrate that SH-SY5Y neuronal cells and HBMEC cells were as permissive for viral replication as Vero E6 and BHK-21 cells, two cell lines that are defective in the antiviral response. The high permissivity of these cells for RVFV replication suggests both cell types may be targeted in vivo and play a role in disease progression. Cytokines produced from SH-SY5Y and HBMEC cells in vitro are similar to the cytokine storm produced in infected rats during the encephalitic stage of disease. MMP-9 may be a potential factor in compromising brain vasculature, and current studies are continuing to evaluate the effect of virus infection on blood brain barrier integrity. Experiments examining the blood brain barrier integrity in infected rats suggest that virus arrives in the CNS via the olfactory bulb prior to breakdown of the blood brain barrier. Taken together, the neuropathological route of infection appears to enter through the olfactory epithelium early after exposure and progresses directly into the brain tissue. The public health significance of this project is supported by the creation of a novel Rift Valley Fever in vitro neuronal model, as well as the exploration of the neuropathogenesis during infection that has previously been unknown