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Virus and cell regulation of reovirus escape from translation inhibition

呼肠孤病毒逃避翻译抑制的病毒和细胞调节

基本信息

批准号：
7981077
负责人：
CATHY L MILLER
金额：
$ 43.06万
依托单位：
IOWA STATE UNIVERSITY
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：
2010-08-16 至 2014-07-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/7981077
关键词：
Address Apoptosis Biology Cell Communication Cells Cellular Stress Characteristics Clinical Trials Communities Complex Cytoplasm Cytoplasmic Granules Cytoplasmic Structures Data Development Disease Double Stranded RNA Virus Double-Stranded RNA Environment Family Family member Gene Expression Genetic Translation Goals Growth Human Immune response Individual Infection Lead Malignant Neoplasms Mammalian Orthoreovirus Messenger RNA Nucleoproteins Nucleosome Core Particle Oncolytic Oncolytic viruses Pathway interactions Peptide Initiation Factors Phase Phosphorylation Phosphotransferases Play Prokaryotic Initiation Factor-2 Property Protein Biosynthesis Protein Synthesis Inhibition Proteins RNA Radiation Recovery Recruitment Activity Regulation Regulatory Pathway Reoviridae Reovirus Research Resistance Role Signal Transduction Stress Structure System Testing Time Translating Translation Initiation Translational Repression Translations Triage Viral Viral Genes Viral Proteins Virus Virus Diseases base chemotherapy design health economics innovation interest killings member neoplastic cell novel oncology pathogen planetary Atmosphere positional cloning prevent prototype public health relevance research study response sodium arsenite tumor virology virus core

项目摘要

DESCRIPTION (provided by applicant): The Reoviridae family of segmented dsRNA viruses includes many members that are of considerable health and economic importance. Additionally, mammalian orthoreoviruses (MRV) are oncolytic viruses that selectively kill tumor cells. Many members of this virus family induce the phosphorylation of translation initiation factor eIF2?, which leads to inhibition of mRNA translation. MRV mRNAs escape cellular translation shutoff. Inhibition of protein synthesis also leads to sequestration of cellular mRNAs and translation initiation factors into cytoplasmic structures termed stress granules (SGs). Recent data suggests that MRV induces SGs during viral entry. As viral infection proceeds, even though eIF2? remains phosphorylated, SGs are disrupted in a manner dependent on protein synthesis. SG disruption also correlates with the formation of virally encoded structures called virus factories (VFs). MRV prevents sodium arsenite (SA) induction of SGs downstream of eIF2? phosphorylation, and strains of MRV that differ in their ability to shutoff host cell translation are all able to translate high levels of mRNA in the presence of SA. This suggests MRV-induced host cell translation shutoff and MRV escape from translational shutoff are independent of each other, and additionally, that escape from shutoff is independent of inhibition of eIF2? phosphorylation. These findings support a hypothesis that SG disruption plays an important role in MRV infection and escape from cellular shutoff of protein synthesis. Experiments in this proposal will test this hypothesis by accomplishing two specific goals. The mechanism of MRV-induced SG disruption will be elucidated by defining the relationship between VFs and SGs, and by determining if VF formation is necessary for SG disruption. Additional experiments will identify MRV proteins required for SG disruption, and determine if MRV infection alters cellular pathways necessary for SG formation. Additionally the mechanism(s) used for MRV translation in the host cell shutoff environment will be investigated by separating the impact of eIF2? phosphorylation and SG formation on MRV translation, and identifying viral proteins and mRNA sequences that are necessary for MRV mRNA translation in the presence of phosphorylated eIF2?. Elucidation of the mechanisms behind this complex virus-host cell interaction will increase our understanding of the basic mechanisms used by these viruses to overcome host cell defenses, and may lead to the development of strategies to either interdict the pathogens in this family using targeted anti-virals, or alternatively, to enhance the oncolytic properties of MRV. PUBLIC HEALTH RELEVANCE: Mammalian orthoreoviruses are members of a family of viruses that includes important human pathogens, and are also oncolytic viruses that selectively kill tumor cells alone or synergistically when combined with radiation or other chemotherapeutic treatments. This proposal is designed to elucidate the mechanisms used by these viruses to escape an important aspect of the host cell defense system that was recently found to play a role in tumor resistance to chemotherapy and radiation. Understanding this complex virus-host cell interaction may lead to the development of targeted anti-virals against the pathogens in this family, or allow educated manipulation of the virus to enhance its individual or synergistic oncolytic properties.

描述（由申请人提供）：分段dsRNA病毒的呼肠孤病毒科家族包括许多具有相当大的健康和经济重要性的成员。此外，哺乳动物正呼肠孤病毒（MRV）是选择性杀死肿瘤细胞的溶瘤病毒。该病毒家族的许多成员诱导翻译起始因子eIF 2？的磷酸化，这导致mRNA翻译的抑制。MRV mRNA逃避细胞翻译关闭。蛋白质合成的抑制还导致细胞mRNA和翻译起始因子被隔离到称为应激颗粒（SG）的细胞质结构中。最近的数据表明，MRV在病毒进入期间诱导SG。随着病毒感染的进行，即使eIF 2？当SGs保持磷酸化时，SGs以依赖于蛋白质合成的方式被破坏。SG破坏还与称为病毒工厂（VF）的病毒编码结构的形成相关。MRV可防止亚砷酸钠（SA）诱导eIF 2下游的SG？在SA的存在下，MRV的磷酸化水平不同，并且在它们阻断宿主细胞翻译的能力方面不同的MRV菌株都能够翻译高水平的mRNA。这表明MRV诱导的宿主细胞翻译关闭和MRV逃离翻译关闭是相互独立的，此外，逃离关闭是独立的抑制eIF 2？磷酸化这些发现支持了一个假设，即SG中断在MRV感染和逃避蛋白质合成的细胞关闭中起着重要作用。本提案中的实验将通过实现两个特定目标来验证这一假设。通过定义VF和SG之间的关系，并确定VF的形成是否是SG中断所必需的，将阐明MRV诱导的SG中断的机制。另外的实验将鉴定SG破坏所需的MRV蛋白，并确定MRV感染是否改变SG形成所需的细胞途径。此外，将通过分离eIF 2的影响来研究在宿主细胞关闭环境中用于MRV翻译的机制？磷酸化和SG形成对MRV翻译的影响，并鉴定在磷酸化eIF 2？存在下MRV mRNA翻译所必需的病毒蛋白和mRNA序列。阐明这种复杂的病毒-宿主细胞相互作用背后的机制将增加我们对这些病毒用于克服宿主细胞防御的基本机制的理解，并可能导致开发使用靶向抗病毒药物阻断该家族中的病原体的策略，或者增强MRV的溶瘤特性。公共卫生相关性：哺乳动物正呼肠孤病毒是包括重要的人类病原体的病毒家族的成员，并且也是选择性地单独杀死肿瘤细胞或当与放射或其他化疗治疗组合时协同杀死肿瘤细胞的溶瘤病毒。该提案旨在阐明这些病毒用于逃避宿主细胞防御系统的一个重要方面的机制，该防御系统最近被发现在肿瘤对化疗和放疗的抵抗中发挥作用。了解这种复杂的病毒-宿主细胞相互作用可能会导致针对该家族中病原体的靶向抗病毒药物的开发，或允许对病毒进行有针对性的操作以增强其个体或协同溶瘤特性。