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: 7934792
• 负责人: Paul Dalling Ling
• 金额: $ 34.54万
• 依托单位: BAYLOR COLLEGE OF MEDICINE
• 依托单位国家: 美国
• 财政年份: 2009
• 资助国家: 美国
• 起止时间: 2009-09-25 至 2010-04-14
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7934792
• 关键词: Acute; Acute Promyelocytic Leukemia; Address; Antiviral Agents; Antiviral Response; Antiviral Therapy; Apoptosis; Biological; Biological Assay; Biological Models; Biology; Cells; Chronic; DNA repair protein; Data; Development; Diagnostic; Enzymes; Fibroblasts; Gene Expression; Gene Expression Regulation; Genome; Goals; Herpesviridae; Herpesviridae Infections; Homologous Gene; Host Defense; Human; Human Herpesvirus 4; Human Herpesvirus 8; Infection; Investigation; Kaposi Sarcoma; Kinetics; Laboratories; Laboratory mice; Light; Link; Lytic Phase; Maintenance; Malignant Neoplasms; Mediating; Modeling; Mus; Nuclear; Organelles; Phenotype; Post-Translational Protein Processing; Production; Proteins; Research; Research Project Grants; Rewards; Rhadinovirus; Role; System; Therapeutic; Transcriptional Activation; Tropism; Viral; Viral Physiology; Viral Proteins; Virion; Virus; Virus Diseases; Virus Replication; Work; base; cofactor; defense response; formylglycinamide; gammaherpesvirus; human disease; in vivo; infected vector rodent; insight; multicatalytic endopeptidase complex; mutant; novel; practical application; response; tool; virus host interaction

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 (γHV68) 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 γHV68 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 γHV68-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 γHV68 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? γHV68 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.

早幼粒细胞核小体(PML NBS)是0.2-1微米的核细胞器，介导一种固有的 针对病毒感染的细胞宿主防御反应。疱疹病毒表达的蛋白质可以调节 PML或PML相关蛋白通过各种策略，包括降解PML或 PML Nb蛋白的重新定位。PML与疱疹病毒相互作用的后果 体内感染仍有待详细研究，这主要是因为该病毒具有物种特异性。 许多人类疱疹病毒。小鼠伽马疱疹病毒68(Hv68)是一种合适的模型 研究病毒宿主相互作用的基本生物学问题，因为它会自然感染小鼠。 最近我们发现，hv68通过依赖蛋白酶体的方式诱导PML降解。 机制和PML的丢失导致在小鼠成纤维细胞中更强大的病毒复制。 令人惊讶的是，我们发现HV68介导的PML降解是由病毒粒子被膜介导的 ORF75c蛋白，与细胞内的甲酰甘氨酰胺核糖氨基转移酶同源 (FGARAT)酶。此外，我们还证明了ORF75c对于感染性病毒的产生是必不可少的。 病毒。ORF75同源物在所有横纹夜蛾病毒中都是保守的，但到目前为止还没有指定的功能。 我们的研究揭示了这种不同寻常的蛋白质在流感病毒生物学中的潜在作用，并提出了 这将是一个有用的模型来研究活体内PML与疱疹病毒的相互作用。目标 本研究的主要目的是：1)确定ORF75c介导PML的机制 降解，2)确定ORF75c如何促进病毒复制周期，以及3) 确定PML在调节急性和慢性运动的动力学和波幅中的作用 体内的疱疹病毒感染。从我们的研究中产生的信息将涉及两个 基本问题。首先，病毒FGARAT蛋白的功能是什么 第二，PML在调节急性和/或慢性疾病中有什么作用 体内疱疹病毒感染？HV68将是解决这些问题的一个有价值的模型系统 人类疱疹病毒和 尤其是伽马疱疹病毒。这项研究的实际应用可能支持这一概念 缺乏PML的系统可以为实验或实验中的病毒感染提供非常敏感的读数 诊断工作。此外，可以想象，增强PML活性的抗病毒疗法 发展起来的。最后，以ORF75为靶点开发新的抗伽马疱疹病毒疗法可能 是一种有益的策略，特别是如果它被发现具有内在的酶功能。