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

基本信息

批准号：
8648977
负责人：
Paul Dalling Ling
金额：
$ 37.99万
依托单位：
BAYLOR COLLEGE OF MEDICINE
依托单位国家：
美国
项目类别：
财政年份：
2010
资助国家：
美国
起止时间：
2010-04-15 至 2016-03-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/8648977
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 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 Therapeutic Transcriptional Activation Tropism Ubiquitin Viral Viral Physiology Viral Proteins Virion Virus Virus Diseases Virus Latency 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

项目摘要

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.

描述（由申请人提供）：临时细胞核体（PML NB）是0.2-1UM核管，介导针对病毒感染的固有细胞宿主防御反应。疱疹病毒表达通过多种策略调节PML或PML相关蛋白的蛋白质，包括PML降解或PML NB NB蛋白的重新定位。体内感染过程中PML疱疹病毒相互作用的后果尚未详细研究，这主要是由于许多人类疱疹病毒的物种特异性的Tropism。鼠伽马疱疹病毒68（？hv68）正在作为研究病毒宿主相互作用的基本生物学问题的合适模型，因为它自然会感染小鼠。最近，我们发现HV68通过蛋白酶体依赖性机制诱导PML降解，而PML的丧失会导致小鼠成纤维细胞中更健壮的病毒复制。令人惊讶的是，我们发现hv68介导的PML降解是由Virion Tegument蛋白ORF75C介导的，该蛋白ORF75C与细胞甲基乙酰酰胺核苷酸氨基转移酶（FGARAT）酶共享同源性。此外，我们已经表明ORF75C对于产生传染病至关重要。 ORF75同源物在所有犀牛病毒中都保存，但到目前为止尚无指定功能。我们的研究阐明了这种不寻常的蛋白质在rhadinovirus生物学中的潜在作用，并表明HV68将是研究体内PML-疱疹病毒相互作用的有用模型。该研究项目的目标是：1）确定ORF75C介导PML降解的机制，2）确定ORF75C如何促进病毒复制周期的贡献，以及3）确定PML在调节VIVO中急性和慢性疱疹病毒感染的动力学和振幅中的作用。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蛋白在伽马病毒生物学中的功能是什么，其次，PML在调节体内调节急性和/或慢性疱疹病毒感染中有什么作用？ HV68将是一个有意义的模型系统，可以以人类疱疹病毒和γ鞘病毒特别困难或不可能解决这些问题。这项研究的实际应用可能支持以下观点：缺乏PML的系统可以在实验或诊断工作中为病毒感染提供非常敏感的读数。此外，可以想象可以开发提高PML活性的抗病毒疗法。最后，针对ORF75来开发新型的抗粉状性抗抑制病毒疗法可能是一个有意义的策略，尤其是在发现它具有内在的酶促功能的情况下。