Neuropathogenesis of Rift Valley fever virus Rift Valley Fever virus (RVFV) infection causes a spectrum of disease including self-limiting febrile illness, hepatitis, and late onset encephalitis. Central nervous system (CNS) involvement results in significant morbidity and mortality and there are no human vaccines or therapeutics in place. Understanding how RVFV disseminates from the site of a mosquito bite in the skin to the CNS is essential knowledge necessary to identify means to prevent or treat this manifestation. Neurotropic viruses have evolved many different mechanisms to access the CNS. These include infection of the brain microvascular endothelial cells (for transcytosis or by causing direct damage), directly traversing the paracellular junctions of the blood brain barrier (BBB), trafficking into the brain within a mobile immune cell, infection of a peripheral nerve and retrograde travel, or via inducing inflammation that loosens endothelial tight junctions and opens the BBB. Therefore, to answer the foundational question of how RVFV disseminates to the CNS following a peripheral exposure, we turn to novel rodent CNS infection models developed in our labs. Key to these models of RVFV neuropathogenesis is the exposure of the mouse to the virus via foot-pad injection to mimic a mosquito bite. In this proposal we will directly address the gaps in our knowledge of how RVFV disseminates, through a series of in vitro and in vivo experiments we will establish the route and mechanisms of invasion of the CNS by RVFV.