Filoviral glycoprotein/cellular protein interactions

描述(申请人提供)：丝状病毒埃博拉病毒(EBOV)和马尔堡病毒(MARV)是毁灭性出血热暴发的罪魁祸首。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高死亡率，这些人畜共患病毒已被列入美国国立卫生研究院生物防御A类名单。结合并介导丝病毒摄取的细胞受体尚未确定。鉴定这种受体和阐明丝状病毒糖蛋白(GP)/受体的相互作用将有助于抗病毒药物的开发和加强对丝状病毒致病机制的认识。这份报告旨在帮助填补这一知识空白。我们已经确定，表面蛋白TIM-1是上皮细胞上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，到目前为止，我们的研究表明，对TIM-1在体内的表达知之甚少。在组织切片中，我们将识别表达TIM-1的细胞，假设TIM-1表达在许多上皮细胞中是常见的。最后，利用TIM-1基因敲除小鼠，我们将在小鼠模型中确定TIM-1对EBOV感染和发病机制的影响。总而言之，这些研究将为未来开发针对这些致命病毒的抗病毒药物铺平道路。 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和不可预测的，这些致命感染的死亡率高达90%，目前没有疫苗或抗病毒治疗可用。在这里，我们确定细胞蛋白TIM-1是埃博拉和马尔堡病毒的受体，并试图了解导致病毒感染的TIM-1和丝病毒糖蛋白之间的分子相互作用。此外，还将进行研究，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病毒结合和进入细胞的细胞蛋白，这将有助于开发可能遏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.