Role of Host Filamin Proteins in Regulating Filovirus Entry and Egress

宿主细丝蛋白在调节丝状病毒进入和排出中的作用

基本信息

  • 批准号:
    10644499
  • 负责人:
  • 金额:
    $ 26.83万
  • 依托单位:
  • 依托单位国家:
    美国
  • 项目类别:
  • 财政年份:
    2023
  • 资助国家:
    美国
  • 起止时间:
    2023-03-10 至 2025-02-28
  • 项目状态:
    未结题

项目摘要

Filoviruses (Ebola [EBOV] and Marburg [MARV]) are zoonotic, emerging pathogens that cause sporadic and global outbreaks of severe hemorrhagic fever in humans and non-human primates. As EBOV and MARV can establish persistent infections in the CNS, semen, eye, and other immunologically privileged sites inaccessible to antibody therapy, and their re-emergence can result in long-term sequelae and death, understanding of host defense mechanisms that could lead to the development of new antiviral therapies is more critical than ever. Our lab is at the forefront of identifying host proteins that interact both physically and functionally with the filovirus VP40 matrix protein, the driving force for virus assembly and egress, to regulate these late stages of virus replication. To better understand the functional filovirus-host interactome, our laboratory has focused on direct interactions between the PPxY Late (L) domain motif conserved in the VP40 proteins of EBOV (eVP40) and MARV (mVP40) and modular WW-domains from select host proteins. In addition to positive regulators of filovirus egress, we have recently identified WW-domain interactors that negatively regulate VP40-mediated budding, including YAP/TAZ, BAG3, and WWOX. While the impact of these negative regulators is likely multifactorial and complex, we have made the intriguing observation that filamin B, a common downstream effector of YAP/TAZ and BAG3, acts as a potential dual regulator of live EBOV/MARV infectivity/entry and live EBOV/MARV egress. As dual role regulation of key stages at opposite ends of the filovirus lifecycle is novel and unexpected, the ultimate goal of this proposal is to determine how host protein filamin B mechanistically impacts the filovirus lifecycle. Filamins are a family of actin crosslinking/stabilizing proteins that regulate actin dynamics at the plasma membrane to control cell migration and morphology, vesicle trafficking, macropinocytosis, and cell division. Notably, macropinocytosis macropinosomes is (MPs) that are densely coated with actin, filamin, and filamin-associated proteins a key entry pathway for filoviruses, as these viruses enter the cell in vesicles termed . In addition, filamins are linked to cellular processes that mimic virion formation and/or egress such as filopodia formation, cell migration, and cytokinesis. Thus, we hypothesize that filamin B regulates infectivity/entry of filoviruses through effects on macropinocytosis, and regulates filovirus budding through effects on egress of filopodia-like filovirus particles. In this exploratory proposal, we propose to investigate the mechanisms by which filamin regulates filovirus infectivity/entry (Aim 1) and egress (Aim 2). Results from these studies will impact the field by identifying a novel host protein(s) whose expression modulates two critical and opposite steps in the filovirus lifecycle; entry and exit, as well as providing a better fundamental understanding of the functional filovirus-host interactome and host defense mechanisms that could lead to the development of new antiviral therapies.
丝状病毒(埃博拉[EBOV]和马尔堡[MARV])是人畜共患的新出现病原体,可引起散发和感染

项目成果

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RONALD N HARTY其他文献

RONALD N HARTY的其他文献

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{{ truncateString('RONALD N HARTY', 18)}}的其他基金

Development of Host- Oriented Therapeutics Targeting Severe Acute Respiratory Syndrome Coronavirus 2 (SARS-CoV-2),
针对严重急性呼吸系统综合症冠状病毒 2 (SARS-CoV-2) 的面向宿主的疗法的开发,
  • 批准号:
    10688262
  • 财政年份:
    2022
  • 资助金额:
    $ 26.83万
  • 项目类别:
Development of Host- Oriented Therapeutics Targeting Severe Acute Respiratory Syndrome Coronavirus 2 (SARS-CoV-2),
针对严重急性呼吸系统综合症冠状病毒 2 (SARS-CoV-2) 的面向宿主的疗法的开发,
  • 批准号:
    10545109
  • 财政年份:
    2022
  • 资助金额:
    $ 26.83万
  • 项目类别:
Role of Host Angiomotin as a Central Regulator of Filovirus Egress and Dissemination
宿主血管动蛋白作为丝状病毒排出和传播的中央调节剂的作用
  • 批准号:
    10380684
  • 财政年份:
    2021
  • 资助金额:
    $ 26.83万
  • 项目类别:
Role of Host Angiomotin as a Central Regulator of Filovirus Egress and Dissemination
宿主血管动蛋白作为丝状病毒排出和传播的中央调节剂的作用
  • 批准号:
    10217843
  • 财政年份:
    2021
  • 资助金额:
    $ 26.83万
  • 项目类别:
Modular Domains of Host Proteins Regulate Filovirus Maturation
宿主蛋白的模块化结构域调节丝状病毒成熟
  • 批准号:
    9517218
  • 财政年份:
    2018
  • 资助金额:
    $ 26.83万
  • 项目类别:
Development of Small Molecule Therapeutics Targeting Hemorrhagic Fever Viruses
针对出血热病毒的小分子疗法的开发
  • 批准号:
    10257889
  • 财政年份:
    2018
  • 资助金额:
    $ 26.83万
  • 项目类别:
Development of Small Molecule Therapeutics Targeting Hemorrhagic Fever Viruses
针对出血热病毒的小分子疗法的开发
  • 批准号:
    10368115
  • 财政年份:
    2018
  • 资助金额:
    $ 26.83万
  • 项目类别:
Development of Small Molecule Therapeutics Targeting Hemorrhagic Fever Viruses
针对出血热病毒的小分子疗法的开发
  • 批准号:
    10599837
  • 财政年份:
    2018
  • 资助金额:
    $ 26.83万
  • 项目类别:
DEVELOPMENT OF SMALL MOLECULE THERAPEUTICS AGAINST RNA VIRUSES
针对 RNA 病毒的小分子疗法的开发
  • 批准号:
    8903846
  • 财政年份:
    2015
  • 资助金额:
    $ 26.83万
  • 项目类别:
Innate Immune Regulation of Intracellular Pathways Involved in Filovirus Budding
丝状病毒出芽涉及的细胞内途径的先天免疫调节
  • 批准号:
    8635498
  • 财政年份:
    2013
  • 资助金额:
    $ 26.83万
  • 项目类别:

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