Endocytosis of Influenza Viruses

描述（由申请人提供）：我们在本申请中的目标是了解细胞中控制流感病毒内吞作用和基因组递送的信号传导事件。我们的基本原理是，了解流感病毒进入细胞所涉及的基本分子事件对于未来抗病毒药物的开发至关重要，这些药物旨在对抗人群中流感病毒感染的年度流行病以及大流行性流感。我们有三个具体的目标：1 -研究流感病毒内吞过程中的细胞信号转导反应。本申请的主要目标之一是了解流感病毒进入细胞途径的调控机制。该项目的最初重点是了解流感病毒如何与细胞的信号网络进行通信。先前已经研究了流感病毒在感染后期对细胞信号传导途径的激活;然而，流感病毒进入期间发生的关键信号传导事件仍然未被探索。2 -研究流感病毒进入细胞的网格蛋白和非网格蛋白途径以及肌动蛋白细胞骨架的作用。我们以前已经证明，流感病毒可以有效地进入细胞在网格蛋白介导的内吞作用的情况下。与网格蛋白和小窝介导的内吞作用的情况相反，关于替代进入途径的信息相对缺乏。本节的主要目的是表征流感病毒进入的非网格蛋白、非小窝途径，并整合我们对极化上皮细胞中网格蛋白和非网格蛋白内吞作用的了解。3 -研究流感病毒内化所需的流感进入期间的上游信号传导事件。我们的目标是了解在流感病毒进入细胞过程中，细胞表面发生的协调内吞运输和信号传导的特定相互作用。流感是一个全球性的重大公共卫生问题。在美国，该病毒每年造成36，000多人死亡，并可能出现新的和潜在致命的病毒株。因此，它被列为NIAID C类优先病原体，用于生物防御和新兴传染病研究。我们相信，我们的工作将为基本了解流感病毒进入提供一个框架，并导致新的抗病毒药物的开发，这仍然是必要的，以打击这种潜在的破坏性病毒性疾病。

DESCRIPTION (provided by applicant): Our goals in this application are to understand the signaling events in the cell that control the endocytosis and genome delivery of influenza virus. Our rationale is that an understanding of the fundamental molecular events involved in the entry of influenza viruses into cells will be critical for the development of future antiviral drugs, designed to combat both the annual epidemics of influenza virus infection in the human population, as well as pandemic influenza. We have three specific aims: 1 - To investigate cellular signaling responses during influenza virus endocytosis. One of the major goals of this application is to understand the regulatory mechanisms underlying the route of influenza virus entry into cells. The initial focus of this project is to understand how influenza virus communicates with the signaling network of the cell. Activation of cellular signaling pathways by influenza virus has previously been studied at late times of infection; however critical signaling events occurring during influenza virus entry remain unexplored. 2 - To investigate the clathrin and non-clathrin routes of influenza virus entry and the role of the actin cytoskeleton. We have previously shown that influenza virus can efficiently enter cells in the absence of clathrin-mediated endocytosis. In contrast to the situation with clathrin- and caveolae-mediated endocytosis, there is a relative paucity of information on alternative routes of entry. The major goals of this section are to characterize the non-clathrin, non-caveolae route of influenza entry, and to integrate our knowledge of both clathrin- and non-clathrin endocytosis in polarized epithelial cells. 3 - To investigate the upstream signaling events during influenza entry that are required for influenza virus internalization. Our goal in this aim is to understand the specific interactions that occur at the cell surface to coordinate endocytic trafficking and signaling during influenza virus entry. Influenza is a major public health problem worldwide. In the United States, the virus is responsible for over 36,000 deaths annually, with the possibility of emergence of new and potentially deadly strains of the virus. As such, it is classed as an NIAID category C priority pathogen for biodefense and emerging infectious disease research. We believe our work will provide a framework for the basic understanding of influenza virus entry and lead to the development of new anti-viral drugs, which are still necessary to combat this potentially devastating viral disease.