Hijacking of cellular pathways by novel tick-borne phlebovirus

 描述(申请人提供)：新的布尼亚病毒严重发热血小板减少综合症病毒(SFTSV)是最近从以发热、血小板减少和出血症状为症状的患者中分离出来的。初步报告的病死率为12-30%，最近还记录了人与人之间传播的证据。这种病毒致病的确切机制仍不清楚。人与人之间传播的可能性、与感染相关的高死亡率以及最近出现的哈特兰病毒--SFTSV的近亲--突显了我们需要增加对这些新病原体如何导致疾病的了解。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(干扰素)反应的有效抑制物。令人惊讶的是，我们发现SFTSV非结构NSS蛋白与I型干扰素反应途径的关键成分RIG-I、TRIM25和TBK1相互作用并重新定位到NSS诱导的细胞质结构中，这一过程涉及泛素和早期内体途径。因此，这个项目的目标是详细了解SFTSV是如何针对这些细胞过程来对抗宿主的先天性免疫反应和建立感染的。这项研究的完成将描述一种新的免疫逃避策略，用于通过SFTSV颠覆宿主的先天免疫，这与目前针对布尼亚病毒的范例不同。我们预计，该项目产生的基本信息将通过定义一种新的免疫逃避策略来颠覆宿主的先天性免疫反应，并很可能为针对SFTSV和其他相关致病RNA病毒的治疗干预和疫苗开发提供新的靶点。

 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.