Filoviral glycoprotein/cellular protein interactions

描述（由申请方提供）：丝状病毒埃博拉（EBOV）病毒和马尔堡（MARV）病毒是造成毁灭性出血热暴发的原因。目前还没有针对这些病原体的疫苗或疗法。由于与感染相关的高发病率和死亡率，这些人畜共患病病毒已被列入NIH生物防御A类名单。尚未鉴定出结合并介导丝状病毒摄取的细胞受体。这种受体的鉴定和丝状病毒糖蛋白（GP）/受体相互作用的阐明将促进抗病毒药物的开发，并提高丝状病毒发病机制的知识。本次提交旨在帮助填补这一知识空白。我们已经确定，表面蛋白TIM-1作为上皮细胞上的丝状病毒的细胞受体。这些研究将阐明人和鼠TIM-1与丝状病毒糖蛋白之间的相互作用，这些糖蛋白是结合和病毒进入内皮细胞所必需的。此外，我们迄今为止的研究表明，TIM-1在体内的表达知之甚少。在组织切片中，我们将鉴定表达TIM-1的细胞，假设TIM-1表达在许多上皮细胞上是常见的。最后，使用Tim-1基因敲除小鼠，我们将确定Tim-1对小鼠模型中EBOV感染和发病机制的影响。总的来说，这些研究将为未来针对这些致命病毒的抗病毒药物的开发铺平道路。 公共卫生相关性：丝状病毒、埃博拉病毒和马尔堡病毒在非洲的爆发是零星的和不可预测的，这些致命的感染具有高达90%的死亡率，而目前没有可用的疫苗或抗病毒治疗。在这里，我们确定了细胞蛋白TIM-1是埃博拉病毒和马尔堡病毒的受体，并试图了解TIM-1和丝状病毒糖蛋白之间的分子相互作用，导致病毒感染。此外，将进行研究以了解TIM-1在埃博拉病毒发病机制中的作用，以便更好地了解介导丝状病毒结合和进入细胞的细胞蛋白，这将有助于开发可能抑制传播和感染的抗病毒疗法。

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.