Mechanisms of actin cytoskeleton modulation by Pneumoviruses

肌动蛋白细胞骨架控制关键的细胞过程，包括细胞形态、运动和细胞间。 沟通。许多病毒病原体利用肌动蛋白的细胞骨架机制，通过各种独特的 促进病毒感染、复制和外泄的机制。目前，这些基因的分子基础 对于大多数病毒，包括肺炎病毒科的成员，病毒机制仍未明确。 一家人。人类呼吸道合胞病毒(RSV)和人类偏肺病毒(HMPV)是不分段的 负链RNA病毒是最近创建的肺炎病毒科的成员。RSV和HMPV 在儿童人群中引起重大疾病，包括毛细支气管炎和下呼吸道感染， 老年人和免疫功能受损的个人。我们团队和其他人最近的研究表明， 肌动蛋白或肌动蛋白相互作用蛋白与肺炎病毒特异性蛋白的相互作用 病毒传播；然而，促进肌动蛋白重排所需的机制和细胞靶点 仍然不为人所知。我们的总体假设是，肺炎病毒之间的一系列特定相互作用 蛋白质和肌动蛋白细胞骨架调节病毒感染的关键步骤，包括形成新的 对病毒在细胞间传播至关重要的结构。我们的协作团队，在病毒学、细胞 生物学、生物化学和结构生物学将通过三个具体目标来检验我们的假设。首先，我们将 剖析RSV和HMPV基质(M)蛋白和调节HMPV的磷蛋白(P)之间的相互作用 感染细胞内的肌动蛋白细胞骨架。第二，我们将确定生物化学和结构基础 HMPV磷酸蛋白/基质/肌动蛋白复合体和RSV P/M/肌动蛋白复合体。最后，我们将确定 细胞间延伸的形成、稳定和在病毒传播中的利用机制。在完成时 在这些研究中，我们希望确定RSV和HMPV与HMPV相互作用的分子机制 在病毒复制过程中调节宿主肌动蛋白细胞骨架，定义这种调节所需的关键元件， 并了解通过细胞间延伸在细胞间传播的分子细节，从而提供 关键的新见解，可能适用于多种病毒系统。

The actin cytoskeleton controls key cellular processes, including cell morphology, motility, and intercellular communication. Many viral pathogens exploit the actin cytoskeletal machinery by a variety of unique mechanisms to facilitate viral infection, replication, and egress. Currently, the molecular underpinnings of these viral mechanisms remain poorly defined for a majority of viruses, including members of the Pneumoviridae family. Human respiratory syncytial virus (RSV) and human metapneumovirus (HMPV) are non-segmented negative strand RNA viruses that are members of the recently created Pneumoviridae family. RSV and HMPV cause significant disease, including bronchiolitis and lower respiratory tract infection in the pediatric population, elderly, and immunocompromised individuals. Recent studies from our groups and others have implicated interactions between actin or actin-interacting proteins and specific pneumovirus proteins in replication and viral spread; however, the mechanisms and cellular targets required for facilitating actin rearrangements remain unknown. Our overall hypothesis is that a cascade of specific interactions between pneumovirus proteins and the actin cytoskeleton regulates key steps in viral infection, including formation of novel structures critical for virus cell-to-cell spread. Our collaborative team, with expertise in virology, cell biology, biochemistry, and structural biology, will test our hypothesis through three specific aims. First, we will dissect the interactions between RSV and HMPV matrix (M) proteins and phosphoproteins (P) that regulate the actin cytoskeleton within an infected cell. Second, we will determine the biochemical and structural basis for HMPV phosphoprotein/matrix/actin complex and RSV P/M/actin complex. Finally, we will determine the mechanisms of intercellular extension formation, stabilization, and utilization in viral spread. At the completion of these studies, we expect to define molecular mechanisms by which RSV and HMPV interact with and modulate the host actin cytoskeleton during virus replication, define key elements needed for this modulation, and understand the molecular details of cell-to-cell spread through intercellular extensions, thus providing critical new insights that may be applicable in multiple viral systems.