Defining the Role of SNX17 in the Entry and Brain Tropism of Multiple Neurotropic Bunyaviruses

Neurotropic bunyaviruses are zoonotic viruses with bi- or tri-segmented negative strand RNA genomes. These viruses, such as Rift Valley Fever Virus, LaCrosse Encephalitis Virus, California Encephalitis Virus, and Jamestown Canyon Virus, are capable of infecting both humans and animals and can cause meningitis and encephalitis by infecting the brain. Although the mechanism by which these viruses infect nerve cells is not fully understood, it is believed to involve their ability to cross the blood-brain barrier and enter the brain. We conducted a genome-wide CRISPR-Cas9 screen using mouse microglial BV2 cells, and identified LRP1 as a receptor for Rift Valley fever virus (RVFV). Interestingly, our screen also identified Sorting nexin 17 (Snx17) as one of the top hits. Our preliminary data demonstrate that SNX17 is an essential host factor for multiple neurotropic bunyavirus infections. The proposed research aims to define the role of Snx17 in the entry and trafficking of the neurotropic bunyaviruses and identify the SNX17-dependent host receptors and entry factors that determine the brain tropism of these viruses. The findings of this study will provide valuable insights into the pathogenesis of neurotropic bunyavirus infections and reveal novel targets for the development of therapeutics aimed at combatting virus-induced encephalitis and mitigating associated brain damage. American Warfighters frequently face the risk of exposure to bunyaviruses such as Rift Valley Fever Virus, Lacrosse Encephalitis Virus, California Encephalitis, and Jamestown Canyon Virus, which are endemic in the areas where they are deployed. These viruses pose a serious threat as they can cause neurological diseases and may have long-term impacts on the well-being of the Warfighter even after their field and combat service. Moreover, these viruses can be easily weaponized for bioterrorism purposes, underscoring the importance of implementing effective preventive measures and treatments. Less