Filoviral glycoprotein/cellular protein interactions

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DESCRIPTION (provided by applicant): The filoviruses Ebola (EBOV) virus and Marburg (MARV) virus are responsible for devastating hemorrhagic fever outbreaks. No vaccines or therapies are currently available against these agents. Because of the high morbidity and mortality associated with infection, these zoonotic viruses have been placed on the NIH Biodefense Category A list. A cellular receptor that binds to and mediates filovirus uptake has not been identified. Identification of such a receptor and elucidation of filoviral glycoprotein (GP)/receptor interactions will facilitate the development of antivirals and enhance knowledge of filoviral pathogenesis. This submission is designed to help fill this knowledge gap. We have identified that the surface protein TIM-1 serves as a cellular receptor for filoviruses on epithelial cells. These studies will elucidate the interactions between human and murine TIM-1 and filovirus glycoproteins that are required for binding and virus entry into endothelial cells. Additionally, our studies to date demonstrated that the expression of TIM-1 within the body is poorly understood. In tissue sections, we will identify cells that express TIM-1 hypothesizing that TIM-1 expression is common on many epithelia. Finally, using a tim-1 knock out mouse, we will determine the impact of Tim-1 on EBOV infection and pathogenesis in the mouse model. In total, these studies will pave the way for the development of future antivirals against these deadly viruses. PUBLIC HEALTH RELEVANCE: Outbreaks in Africa of the filoviruses, Ebola virus and Marburg virus, are sporadic and unpredictable with these deadly infections having mortality rates as high as 90% with no current vaccines or antiviral treatments available. Here, we identify that the cellular protein TIM-1 is a receptor for both Ebola and Marburg virus and seek to understand the molecular interactions between TIM-1 and filovirus glycoproteins that lead to virus infection. Further, studies will be performed to understand the role of TIM-1 in Ebola virus pathogenesis for a better understanding of cellular proteins that mediate filovirus binding and entry into cells that will facilitate the development of antiviral therapies potentially curbing transmission and infection.