Endocytosis of Influenza Viruses

描述(申请人提供)：我们在本申请中的目标是了解控制流感病毒的内吞作用和基因组传递的细胞中的信号事件。我们的理由是，对流感病毒进入细胞所涉及的基本分子事件的了解将对未来抗病毒药物的开发至关重要，该药物旨在对抗每年在人类群体中流行的流感病毒感染，以及大流行流感。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反应。这项应用的主要目标之一是了解流感病毒进入细胞的潜在调控机制。该项目最初的重点是了解流感病毒如何与细胞的信号网络进行通信。以前已经研究过流感病毒在感染后期激活细胞信号通路；然而，在流感病毒进入过程中发生的关键信号事件仍未被探索。2-研究流感病毒进入细胞内的包络蛋白和非包络蛋白途径以及肌动蛋白细胞骨架的作用。我们之前已经证明，流感病毒可以在没有网状蛋白介导的内吞作用的情况下有效地进入细胞。与网状蛋白和小窝介导的内吞作用相比，关于替代进入途径的信息相对较少。这一部分的主要目标是描述流感进入的非分子筛蛋白、非囊泡的途径，并整合我们对极化上皮细胞中分子筛蛋白和非分子筛蛋白内吞作用的知识。3-调查流感进入期间流感病毒内化所需的上游信号事件。我们的目标是了解在细胞表面发生的特定相互作用，以协调流感病毒进入过程中的内吞运输和信号传递。流感是世界范围内的一个主要公共卫生问题。在美国，该病毒每年造成超过3.6万人死亡，并有可能出现新的、可能致命的病毒株。因此，它被归类为NIAID C类优先病原体，用于生物防御和新出现的传染病研究。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，并导致开发新的抗病毒药物，这些药物对于抗击这种潜在的破坏性病毒疾病仍然是必要的。

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.