Alphavirus nsP3 protein: roles of intrinsically disordered region in virus replication and pathogenesis

甲病毒 nsP3 蛋白：本质紊乱区域在病毒复制和发病机制中的作用

基本信息

批准号：
9089999
负责人：
ELENA I FROLOVA
金额：
$ 36.75万
依托单位：
UNIVERSITY OF ALABAMA AT BIRMINGHAM
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 2020-05-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/9089999
关键词：
Alphavirus Alphavirus Infections American Animal Model Antiviral Therapy Arbovirus Encephalitis Binding Biochemical Biology Bioterrorism C-terminal Capsid Categories Cell Communication Cell physiology Cells Centers for Disease Control and Prevention (U.S.)Central America Characteristics Complex Data Development Disease Eastern Equine Encephalitis Virus Encephalitis Viruses Environment Epidemic Equine Encephalomyelitis Equus caballus Exhibits Family Generations Genome Goals Health Integration Host Factors Investigation Knowledge Lead Mediating Methods Minor Modification Molecular Morphology Mutate Mutation Neurological outcome Nonstructural Protein North America Pathogenesis Pathogenicity Proline Proteins Public Health RNA replication Research Research Proposals Role Sequence Homology Sindbis Virus South America Structural Genes Testing Therapeutic Therapeutic Intervention Togaviridae Vaccines Venezuelan Venezuelan Equine Encephalomyelitis Viral Pathogenesis Viral Proteins Virion Virus Virus Diseases Virus Replication attenuation base cell type design epizootic farnesoid X-activated receptor flexibility human disease in vivo macromolecule member mutant novel strategies novel therapeutics novel vaccines protein complex user-friendly vaccine candidate viral RNA virus pathogenesis virus tropism

项目摘要

DESCRIPTION (provided by applicant): The Alphavirus genus in the Togaviridae family contains over 30 members, many of which represent an unquestionable, but often underappreciated, public health threat. In spite of the ability of alphaviruses to cause broad epidemics and severe human diseases, no efficient vaccines or therapeutic means have been developed against any alphavirus infections. This is primarily a result of our insufficient knowledge of their biology, mechanism of replication and interaction with the host. Alphavirus-host cell interaction is particularly poorly understood. In our recent studies, we have made new steps towards understanding functions of one of four alphavirus nonstructural proteins, nsP3. This protein has unique structural characteristics and so far, no functions have yet been assigned to it. Our preliminary data demonstrate that alphavirus nsP3 exhibits both common and virus- and host-specific functions in adaptation of cellular environment for efficient virus replication. These functions are mediated by its carboxy terminal, hypervariable domain, which is intrinsically disordered and thus, can interact with a wide range of host factors. In the research covered by this proposal, we will use a combination of biochemical, molecular and virological methods to characterize cellular proteins interacting primarily with the nsP3 of encephalitogenic Venezuelan equine encephalitis and eastern equine encephalitis viruses. We will perform detailed mechanistic studies of the nsP3-host protein complexes and delineate their functions in virus-specific modifications of the intracellular environment and defining viral pathogenesis. Investigation of the mechanism of the nsP3 functions will have a strong impact on understanding alphavirus replication and will provide new targets for development of antiviral therapy and new approaches for rational design of alphavirus vaccines candidates.

描述（由适用提供）：Togaviridae家族中的Alphavirus属包含30多名成员，其中许多成员代表了毫无疑问但通常不被征服的公共卫生威胁。尽管α病毒引起广泛的流行病和严重的人类疾病的能力，但仍未针对任何α病毒感染开发有效的疫苗或治疗手段。这主要是由于我们对生物学的了解不足，复制机制和与宿主相互作用的结果。 α病毒宿主细胞相互作用尤其了解。在我们最近的研究中，我们为理解四种α非结构蛋白之一的功能做出了新的步骤，NSP3。该蛋白质具有独特的结构特征，到目前为止，尚未分配任何功能。我们的初步数据表明，α病毒NSP3在适应细胞环境中具有常见和病毒和宿主特异性功能，以进行有效的病毒复制。这些功能是由其羧基末端的高变量域介导的，该域本质上是无序的，因此可以与广泛的宿主因子相互作用。在该提案所涵盖的研究中，我们将使用生化，分子和病毒学方法的组合来表征主要与脑生成委内瑞拉委内瑞拉省脑炎和东部等效性脑炎病毒病毒的细胞蛋白相互作用。我们将对NSP3-宿主蛋白复合物进行详细的机械研究，并描绘它们在细胞内环境的病毒特异性修饰中的功能并定义病毒发病机理。对NSP3功能机制的研究将对理解α病毒复制产生强大的影响，并将为开发抗病毒药疗法的新目标和新方法，用于合理设计α病毒疫苗候选者。