Emerging virus-host cell protein interaction networks

新兴的病毒-宿主细胞蛋白质相互作用网络

• 批准号: 8964885
• 负责人: ROBERT A DAVEY
• 金额: $ 62.46万
• 依托单位: PURDUE UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2015
• 资助国家: 美国
• 起止时间: 2015-05-04 至 2020-03-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8964885
• 关键词: Address; Affinity Chromatography; Agonist; Antiviral Agents; Arenavirus; Benchmarking; Binding; Biochemical; Bioinformatics; Biological; Biological Assay; Categories; Cell Communication; Cell Culture Techniques; Cells; Complex; Containment; Crimean-Congo Hemorrhagic Fever Virus; Data; Data Set; Dengue Virus; Dependence; Development; Disease Outbreaks; Disease Outcome; Drug effect disorder; Ebola virus; Environment; Family; Filovirus; Frankfurt-Marburg Syndrome Virus; Genotype; Goals; Health; Hepatitis C virus; Human; Human Virus; Individual; Infection; Informatics; Junin virus; Laboratories; Lassa Fever; Lassa fever virus; Lead; Life; Life Cycle Stages; Location; Maps; Mass Spectrum Analysis; Methods; Modeling; Molecular; Mus; National Institute of Allergy and Infectious Disease; National Security; Orthobunyavirus; Pathogenesis; Pathway interactions; Preparation; Principal Investigator; Protein Binding; Proteins; RNA Interference; RNA Viruses; Recruitment Activity; Reporting; Research; Risk; Role; Signal Pathway; Techniques; Technology; Testing; Tissues; Viral Hemorrhagic Fevers; Viral Proteins; Virus; Virus Diseases; Virus Replication; Work; Yeasts; cellular targeting; cofactor; experience; gammaherpesvirus; genome-wide; hemorrhagic fever virus; improved; inhibitor/antagonist; insight; interest; mortality; network models; novel strategies; pathogen; programs; protein protein interaction; public health relevance; screening; small molecule; virus host interaction; yeast two hybrid system

 DESCRIPTION (provided by applicant): The overall goal of this proposal is to identify and characterize cellular proteins that bind to viral hemorrhagic fever viruses. Specifically, we focus on RNA viruses from four families: the filoviruses Ebolavirus and Marburg virus; the Arenaviruses Junin virus and Lassa Fever virus; and the Bunyavirus Crimean-Congo hemorrhagic fever virus. These emerging viruses pose significant risks to human health and national security. While each differs in the types of proteins encoded, they share similar disease outcomes, causing severe, often fatal infections in humans; all are classified as NIAID Category A Priority Pathogens. Due to the high level containment needed to work with many of them, there is a significant gap in our understanding of these viruses and no specific, approved therapies are currently available. Like all viruses, these emerging viruses rely on host cell proteins in order to replicate. This dependence represents a potential "Achilles heel" in the virus life cycle that may be exploited to develop new approaches to treat viral infections. However, only a small number of virus-host cell protein interactions have been reported for the viruses in this study, and no systematic analysis of emerging virus-host cell protein interactions has been performed. In this project we develop and evaluate high quality maps of emerging virus-human protein interactions. In Aim 1 we use complementary yeast two-hybrid screening and co-affinity purification plus mass spectrometry approaches to identify cellular proteins that bind to emerging viruses and closely related non-pathogenic viruses from the same family. In aim 2 we identify shared and virus-specific features of the host cell interaction networks of emerging viruses. We use orthologonal protein-protein interaction assays to identify shared and virus specific interactions within each virus family. To gain confidence in these results, each assay is benchmarked against the human positive and random reference sets. We then employ informatic approaches to discover pathways that targeted preferentially by emerging viruses, develop tissue-specific virus-host cell protein interaction networks, and identify small molecule agonists or antagonists predicted to inhibit virus replication. In aim 3, we test the predictions generated through the bioinformatic analyses. A subset of high-interest cellular proteins targeted by multiple viruses will be experimentally interrogated for their contribution to infectio using RNA interference. State-of-the-art molecular techniques are then employed to determine the mechanisms by which they contribute to virus replication. Virus- and tissue-specific interactions are evaluated for their contribution to virus replication and their effect on cellular signaling pathways. Finally, small molecule inhibitors identified in our network models are evaluated for their effect on virus replication in cell culture. The data generated from this projet will improve our understanding of the functions of individual viral proteins, provide insight into the overall strategies used by viral hemorrhagic fever virus to interface with their host cells, an may lead to the discovery of new targets for treatments of emerging viruses.

 描述：我们的整体目标是识别和表征与病毒的细胞蛋白 埃博氏病毒和马堡病毒;这些新兴病毒在编码类似的蛋白质中，它们具有相似的疾病，造成了疾病的疾病，这些疾病的疾病是显着的对于与许多人一起使用的高级杂物，我们对病毒的理解存在很大的差距，并且没有像所有病毒一样，这些新兴病毒依赖于宿主细胞蛋白来复制这种依赖性。病毒中的“阿喀琉斯高跟鞋” 在这项研究中，已经报道了病毒感染的新方法。相互作用新兴病毒的网络。 AIM 3中的复制。病毒复制及其对细胞的影响。 信号通路。我们网络模型中的小分子抑制剂对培养物中的病毒复制的影响。 ，可能会导致靶标治疗新出现的病毒。