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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：
RONALD N HARTY
金额：
$ 26.83万
依托单位：
UNIVERSITY OF PENNSYLVANIA
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

来源：
https://reporter.nih.gov/project-details/10644499
关键词：
Actins Affect Antibody Therapy Antiviral Therapy BAG3 gene Biochemical Biological Assay Cell Fractionation Cell Separation Cell division Cell membrane Cell physiology Cells Cellular Morphology Cessation of life Complex Cytokinesis Development Disease Outbreaks Ebola Ebola virus Eye Family Filopodia Filovirus Future Goals HIV-1 Host Defense Mechanism Human Immunologics Infection Integrins Laboratories Life Cycle Stages Link Liquid substance Magnetism Mammalian Cell Marburgvirus Mediating Membrane Microscopy Molecular Pathway interactions Process Proteins Proteome Reagent Recombinants Regulation Ribonucleases Role Seminal fluid Site Small Interfering RNA Testing Therapeutic Intervention Total Internal Reflection Fluorescent Vesicle Vesicular stomatitis Indiana virus Viral Viral Hemorrhagic Fevers Virion Virus Virus Assembly Virus Diseases Virus Replication Zoonoses cell motility chronic infection combat confocal imaging crosslink driving force emerging pathogen extracellular filamin insight link protein long-term sequelae member nonhuman primate novel particle protein crosslink trafficking ubiquitin-protein ligase virus host interaction

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