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（由申请人提供）：最近从出现发烧、血小板减少和出血症状的患者中分离出新型布尼亚病毒严重发烧血小板减少综合症病毒（SFTSV），据报道初始病死率为 12-30%，并且有证据表明该病毒可能导致人死亡。最近还记录了这种病毒引起疾病的确切机制，即人际传播的可能性。与感染相关的高死亡率以及最近出现的SFTSV近亲Heartland病毒，凸显了我们需要增加对这些新病原体如何引起疾病的了解。此外，它还强调需要针对这些新出现的病原体制定治疗干预措施。我们已经确定 SFTSV 非结构 NSs 蛋白是宿主干扰素 (IFN) 反应的有效抑制剂。令人惊讶的是，我们发现 SFTSV 非结构 NSs 蛋白与宿主干扰素 (IFN) 相互作用并重新定位。 RIG-I、TRIM25 和 TBK1（I 型 IFN 应答途径的关键成分）在涉及泛素和早期内体途径的过程中进入 NSs 诱导的细胞质结构。因此，该项目的目标是提供对 NSs 诱导的细胞质结构的详细了解。 SFTSV 如何针对这些细胞过程来对抗宿主先天免疫反应并建立感染。完成本研究将描述一种独特的 SFTSV 颠覆宿主先天免疫的新型免疫逃避策略。我们预计该项目中产生的基本信息将通过定义颠覆宿主先天免疫反应的新型免疫逃避策略来推动该领域的发展，并很可能为针对 SFTSV 和其他病毒的治疗干预和疫苗开发提供新的目标。相关的致病性RNA病毒。