The effect of infection route on disease outcome in rats infected with Rift Valley fever virus

Rift Valley fever virus (RVFV) is a mosquito-borne pathogen which has the potential of causing severe outbreaks in both livestock and humans. These outbreaks are currently confined mostly in Africa and the Arabian Peninsula, but have the potential to spread to many locations. Symptomatic humans can experience a wide range of disease features, but most infected people develop a self-limited febrile illness (fever and body aches). In 1-2% of cases, more severe forms develop, including encephalitis or hemorrhagic fever. The case fatality rate of the encephalitic and hemorrhagic form of the disease is 50%. Because no licensed vaccine exists to prevent this viral infection, further research on the pathogenesis of the virus must be completed to further our understanding. The most poorly understood form of RVF is the encephalitic form. Our lab uses a rat model of lethal encephalitis involving aerosol infection with RVFV. This study has 2 aims: 1) To better understand disease caused in rats after different routes of infection. Our lab’s research on RVFV has to date focused primarily on the aerosol infection route, so this study implemented alternate routes of infection to map the outcome of disease progression. 2) To measure the vascular integrity of the brain in aerosol infected rats to determine if breakdown of the blood brain barrier occurs. Our results from Aim 1 demonstrated that intranasal and aerosol infections caused the highest lethality. Intragastric and intratracheal routes did not consistently establish lethal infection in the animals. Confirming prior results, the subcutaneous route of infection established the lowest mortality in Lewis rats, with nearly all rats surviving infection after receiving a high dose. For Aim 2, we found that the blood brain barrier breaks down after viral penetration into the brain between 4-6 days post infection. This breakdown was especially evident in the olfactory bulb, cerebellum, and cortex of infected animals. The public health significance of this project is directly related to the exploration of the neuropathogenesis of Rift Valley fever virus, which is currently unknown. Understanding how RVFV establishes infection in host species is the first critical step in vaccine or therapeutic development