Hijacking of cellular pathways by novel tick-borne phlebovirus

新型蜱传白蛉病毒劫持细胞通路

基本信息

批准号：
9088328
负责人：
Patricia Veronica Aguilar
金额：
$ 19.26万
依托单位：
UNIVERSITY OF TEXAS MED BR GALVESTON
依托单位国家：
美国
项目类别：
财政年份：
2015
资助国家：
美国
起止时间：
2015-06-15 至 2018-05-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/9088328
关键词：
Antiviral Agents Asia Autophagocytosis Case Fatality Rates Cell physiology Cells China Confocal Microscopy Cytoplasmic Structures Data Degradation Pathway Development Disease Early Endosome Endoplasmic Reticulum Endosomes Environment Fatality rate Fever Future Genes Genus Phlebovirus Goals Golgi Apparatus Health Heartland virus Host Defense Human Immune Immune response Infection Interferon Type I Interferon-beta Interferons Japan Knowledge Korea Lead Ligands Mediating Molecular Natural Immunity Nucleoproteins Orthobunyavirus Outcome Pathogenesis Pathway interactions Patients Persons Polymerase Preventive Intervention Process Proteins RNA Viruses Reporting Research Role Signal Transduction Signaling Protein Structure Syndrome TANK-binding kinase 1 TRIM25 gene Therapeutic Therapeutic Intervention Thrombocytopenia Ticks Ubiquitin Ubiquitination United States Vaccines Viral Hemorrhagic Fevers Viral Nonstructural Proteins Virus Virus Diseases Virus Replication base combat defined contribution genetic regulatory protein inhibitor/antagonist monocyte mortality novel pathogen prevent promoter response sensor therapeutic vaccine transmission process ubiquitin-protein ligase vaccine development viral RNA virus pathogenesis

项目摘要

DESCRIPTION (provided by applicant): The novel bunyavirus Severe Fever Thrombocytopenia Syndrome virus (SFTSV) was recently isolated from patients presenting with fever, thrombocytopenia and hemorrhagic manifestations. An initial case fatality rate of 12-30% has been reported and evidence of person-to-person transmission has also been recently documented. The exact mechanism by which this virus causes disease is still unknown. The possibility of person-to-person transmission, the high fatality rate associated with infection and the recent emergence of Heartland virus, a close relative of SFTSV, highlights the need to increase our knowledge on how these new pathogens cause diseases. Furthermore, it also underscores the need to develop therapeutic interventions against these emerging pathogens. We have determined that the SFTSV nonstructural NSs protein is a potent inhibitor of host interferon (IFN) responses. Astonishingly, we found that the SFTSV nonstructural NSs protein interacts with and relocalizes RIG-I, TRIM25 and TBK1, key components of the Type I IFN response pathway, into NSs-induced cytoplasmic structures in a process that involves ubiquitin and the early endosome pathway. Thus, the goal of this project is to provide a detailed understanding of how these cellular processes are targeted by SFTSV to counteract host innate immune responses and establish infection. Completion of this study will describe a novel immune evasion strategy for subversion of host innate immunity by SFTSV that is distinct from the current paradigm for bunyaviruses. We expect the fundamental information generated in this project will advance the field by defining a novel immune evasion strategy for subversion of host innate immune responses and very likely provide new targets for therapeutic interventions and vaccine development against SFTSV and other related pathogenic RNA viruses.

描述（由适用提供）：新型Bunyavirus严重的发烧血小板减少综合征病毒（SFTSV）从表现出发烧，血小板减少症和出血性表现的患者中分离出来。据报道，最初的病例死亡率为12-30％，最近还记录了人与人传播的证据。该病毒引起疾病的确切机制仍然未知。人与人传播的可能性，与感染相关的高死亡率以及SFTSV近亲的Heartland病毒最近出现的可能性，强调了我们对这些新病原体如何引起疾病的了解的需求。此外，它还强调了针对这些新兴病原体开发治疗干预措施的必要性。我们已经确定SFTSV非结构性NSS蛋白是宿主干扰素（IFN）反应的潜在抑制剂。令人惊讶的是，我们发现SFTSV非结构性NSS蛋白与RIG-I，TRIM25和TBK1的相互作用并重新定位，这是I型IFN响应途径的关键成分，在涉及泛素和早期胚胎的过程中，在NSS诱导的细胞质结构中与NSS诱导的细胞质结构相互作用。这是该项目的目标是详细了解SFTSV如何针对这些细胞过程来抵消宿主先天免疫反应和建立感染。这项研究的完成将描述一种新型的免疫进化策略，用于通过SFTSV颠覆宿主先天免疫免疫，这与当前的Bunyaviruses范式不同。我们预计，该项目中产生的基本信息将通过定义一种颠覆宿主先天免疫反应的新型免疫进化策略来推进该领域，并且很可能为治疗干预措施和针对SFTSV和其他相关病原RNA病毒的疫苗开发提供了新的靶标。