Evasion of intrinsic antiviral host cell responses by herpesviruses

疱疹病毒逃避宿主细胞固有的抗病毒反应

• 批准号: 7884862
• 负责人: Paul Dalling Ling
• 金额: $ 30.7万
• 依托单位: BAYLOR COLLEGE OF MEDICINE
• 依托单位国家: 美国
• 财政年份: 2010
• 资助国家: 美国
• 起止时间: 2010-04-15 至 2015-03-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7884862
• 关键词: Acute; Acute Promyelocytic Leukemia; Address; Antiviral Agents; Antiviral Response; Antiviral Therapy; Apoptosis; Appearance; Biological; Biological Assay; Biological Models; Biology; CREB1 gene; Cell Cycle; Cell Nucleus; Cells; Chronic; DNA Damage; DNA repair protein; Data; Development; Diagnostic; Employee Strikes; Enzymes; Fibroblasts; Frequencies; Gene Expression; Gene Expression Regulation; Genome; Goals; Herpesviridae; Herpesviridae Infections; Homologous Gene; Host Defense; Human; Human Herpesvirus 4; Human Herpesvirus 8; Immunofluorescence Microscopy; Infection; Investigation; Kaposi Sarcoma; Kinetics; Laboratories; Laboratory mice; Light; Link; Lytic Phase; Maintenance; Malignant Neoplasms; Mediating; Modeling; Mus; Nuclear; Organelles; Phase; Phenotype; Post-Translational Protein Processing; Production; Proteins; Research; Research Project Grants; Rewards; Rhadinovirus; Role; Staging; System; TP53 gene; Therapeutic; Transcriptional Activation; Tropism; Ubiquitin; Viral; Viral Physiology; Viral Proteins; Virion; Virus; Virus Diseases; Virus Replication; Work; base; cell type; cofactor; defense response; formylglycinamide; gammaherpesvirus; heterochromatin-specific nonhistone chromosomal protein HP-1; human disease; in vivo; infected vector rodent; insight; multicatalytic endopeptidase complex; mutant; novel; practical application; public health relevance; response; tool; virus host interaction

DESCRIPTION (provided by applicant): Promyelocytic nuclear bodies (PML NBs) are 0.2-1um nuclear organelles that mediate an intrinsic cellular host defense response against virus infections. Herpesviruses express proteins that modulate PML or PML-associated proteins by a variety of strategies, including degradation of PML or relocalization of PML NB proteins. The consequences of PML-herpesvirus interactions during infection in vivo have yet to be investigated in detail, largely because of the species-specific tropism of many human herpesviruses. Murine gammaherpesvirus 68 (?HV68) is emerging as a suitable model to study basic biological questions of virus host interactions because it naturally infects mice. Recently we have found that ?HV68 induces PML degradation through a proteasome-dependent mechanism and that loss of PML results in more robust virus replication in mouse fibroblasts. Surprisingly, we found that ?HV68-mediated PML degradation is mediated by the virion tegument protein ORF75c, which shares homology with the cellular formylglycinamide ribotide amidotransferase (FGARAT) enzyme. In addition, we have shown that ORF75c is essential for production of infectious virus. ORF75 homologs are conserved in all rhadinoviruses but so far have no assigned functions. Our studies shed light on a potential role for this unusual protein in rhadinovirus biology and suggest that ?HV68 will be a useful model for investigation of PML-herpesvirus interactions in vivo. The goals of this research project are to: 1) determine the mechanism by which ORF75c mediates PML degradation, 2) to determine how ORF75c contributes to the viral replication cycle, and 3) to determine the role of PML in modulating the kinetics and amplitude of acute and chronic herpesvirus infection in vivo. The information generated from our studies will address two fundamental questions. First, what is the function of the viral FGARAT proteins for gammaherpesvirus biology and second, what role does PML have in modulating acute and/or chronic herpesvirus infections in vivo? ?HV68 will be a rewarding model system to address these questions in ways that would be significantly more difficult or impossible with human herpesviruses and gammaherpesviruses in particular. Practical applications from this research might support the notion that PML-deficient systems can offer a very sensitive readout for viral infection in experimental or diagnostic work. In addition, antiviral therapies that enhance PML activities could conceivably be developed. Finally, targeting ORF75 for developing novel anti-gammaherpesvirus therapeutics might be a rewarding strategy, especially if it is found to possess intrinsic enzymatic functions. PUBLIC HEALTH RELEVANCE: Human gammaherpesviruses, exemplified by Epstein-Barr virus and Kaposi's Sarcoma herpesvirus (EBV and KSHV), are significant causes of human disease, including cancer. We will utilize murine gammaherpesvirus 68 (?HV68) to help unravel mechanisms by which gammaherpesviruses evade intrinsic host defenses through the activity of an unusual viral protein ORF75, which is conserved in all gammaherpesviruses. Our studies will yield new insights into virus-host interactions that modulate viral infections and possibly identify new viral targets for development of novel antiviral therapeutics.

描述（由申请人提供）：早幼粒细胞核体（PML NB）是0.2- 1 μ m的核细胞器，介导针对病毒感染的内在细胞宿主防御反应。疱疹病毒通过多种策略表达调节PML或PML相关蛋白的蛋白，包括PML的降解或PML NB蛋白的重新定位。体内感染期间PML-疱疹病毒相互作用的后果尚未详细研究，主要是因为许多人类疱疹病毒的种属特异性嗜性。鼠γ疱疹病毒68（？HV 68）是研究病毒宿主相互作用的基本生物学问题的合适模型，因为它自然感染小鼠。最近我们发现，？HV 68通过蛋白酶体依赖性机制诱导PML降解，PML的缺失导致小鼠成纤维细胞中更稳健的病毒复制。令人惊讶的是，我们发现？HV 68介导的PML降解由病毒体被膜蛋白ORF 75 c介导，ORF 75 c与细胞甲酰甘氨酰胺核糖核苷酸酰胺转移酶（FGARAT）具有同源性。此外，我们已经证明ORF 75 c对于感染性病毒的产生是必需的。ORF 75同源物在所有的鼻状病毒中是保守的，但迄今为止还没有指定的功能。我们的研究揭示了这种不寻常的蛋白质在鼻病毒生物学中的潜在作用，并表明？HV 68将是一个有用的模型，研究PML-疱疹病毒在体内的相互作用。本研究项目的目标是：1）确定ORF 75 c介导PML降解的机制，2）确定ORF 75 c如何促进病毒复制周期，3）确定PML在体内调节急性和慢性疱疹病毒感染的动力学和幅度中的作用。从我们的研究中产生的信息将解决两个基本问题。首先，病毒FGARAT蛋白对γ疱疹病毒生物学的功能是什么，其次，PML在体内调节急性和/或慢性疱疹病毒感染中的作用是什么？? HV 68将是一个有益的模型系统，以解决这些问题的方式，将显着更困难或不可能与人类疱疹病毒和γ疱疹病毒，特别是。这项研究的实际应用可能支持这样一种观点，即PML缺陷系统可以在实验或诊断工作中提供非常灵敏的病毒感染读数。此外，增强PML活性的抗病毒疗法也有望开发出来。最后，针对ORF 75开发新型抗γ疱疹病毒治疗方法可能是一种有益的策略，特别是如果发现它具有内在的酶功能。 公共卫生相关性：人γ疱疹病毒，例如爱泼斯坦-巴尔病毒和卡波西肉瘤疱疹病毒（EBV和KSHV），是人类疾病（包括癌症）的重要原因。我们将利用鼠γ疱疹病毒68（？HV 68），以帮助阐明γ疱疹病毒通过一种不寻常的病毒蛋白ORF 75的活性逃避宿主内在防御的机制，ORF 75在所有γ疱疹病毒中都是保守的。我们的研究将对调节病毒感染的病毒-宿主相互作用产生新的见解，并可能确定新的病毒靶点，用于开发新的抗病毒治疗药物。