Virus-host interactions governing alpha-herpesvirus genome delivery and neuroinvasion

控制α-疱疹病毒基因组传递和神经侵袭的病毒-宿主相互作用

• 批准号: 10569016
• 负责人: GARY Edward PICKARD
• 金额: $ 48.39万
• 依托单位: NORTHWESTERN UNIVERSITY AT CHICAGO
• 依托单位国家: 美国
• 财政年份: 2020
• 资助国家: 美国
• 起止时间: 2020-02-01 至 2025-01-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10569016
• 关键词: Advanced Development; Afferent Neurons; Alphaherpesvirinae; Animals; Antiviral Agents; Axonal Transport; Binding; Binding Sites; Biological; Bite; Brain; Capsid; Cell Culture Techniques; Cell Nucleus; Cells; Cellular biology; Complex; DNA Viruses; Data; Disease; Dsh protein; Encephalitis; Event; Eye; Family; Family member; Gene Delivery; Genetic; Genome; Goals; Herpes zoster disease; Herpesviridae; Herpesvirus 1; Herpesvirus Type 3; Human Herpesvirus 2; Immunocompetent; Individual; Infection; Integration Host Factors; Invaded; Keratitis; Link; Malignant Neoplasms; Maps; Mass Spectrum Analysis; Medical; Methods; Modeling; Modification; Monitor; Morbidity - disease rate; Mothers; Mutagenesis; Nervous System; Neurons; Newborn Infant; Nuclear; Oncolytic; Pattern; Peripheral; Phenotype; Phosphotransferases; Positioning Attribute; Property; Protein Kinase; Proteins; Puncture procedure; Recombinants; Resources; Rodent; Role; Simplexvirus; Synapses; Syringes; Technology; Tracer; Trauma; Vaccines; Validation; Varicellovirus; Viral; Viral Genome; Viral Vector; Virus; Virus Diseases; WNT Signaling Pathway; Work; defined contribution; design; human pathogen; in vivo; latent infection; mad itch virus; member; mortality; neonatal infection; nervous system infection; neural; neuroproteomics; neurovirulence; novel; pathogen; permissiveness; programs; recombinant virus; repaired; tissue tropism; trait; ubiquitin isopeptidase; vector; virus host interaction

PROJECT SUMMARY Spread of neuroinvasive herpesviruses from sensory neurons to the eye, brain, or from mother to newborn, are significant causes of morbidity and mortality. Herpes simplex virus type 1 (HSV1) and pseudorabies virus (PRV) are representative members of the two genuses of mammalian neuroinvasive herpesviruses (simplexviruses & varicelloviruses). These viruses are dependent upon spread to the nervous system to establish life-long latent infections, yet very little is known regarding the neuroinvasive mechanism that underlies this remarkable trait. We propose to study the virus neuroinvasive machinery with the intent to: (i) decipher how these viruses invade the nervous system, (ii) understand the intrinsic barriers to neural infection that these viruses evade, and (iii) produce and characterize viruses lacking the neuroinvasive property as potential vaccines and recombinant vectors. These studies are designed to identify the virus-cellular interactions that promote virus genome delivery to the nuclei of non-neuronal and neuronal cells, and the corresponding intrinsic defenses that keep most pathogens at bay. We include preliminary data demonstrating that this path-breaking collaborative study has far-reaching medical and biological implications.

项目摘要 神经侵袭性疱疹病毒从感觉神经元传播到眼睛、大脑或从母亲传播到 新生儿是发病和死亡的重要原因。单纯疱疹病毒1型（HSV 1）和 伪狂犬病病毒（Pseudorabies virus，PRV）是哺乳动物两个属的代表性成员， 神经侵入性疱疹病毒（单纯疱疹病毒和水痘病毒）。这些病毒依赖于 传播到神经系统，建立终身潜伏感染，但很少有人知道， 这一显著特征背后的神经侵入机制。我们打算研究这种病毒 神经侵入性机器，其目的是：（i）破译这些病毒如何侵入神经系统， (ii)了解这些病毒逃避的神经感染的内在障碍，以及（iii）产生和 将缺乏神经侵入特性的病毒表征为潜在的疫苗和重组载体。 这些研究旨在确定促进病毒基因组递送的病毒-细胞相互作用 非神经元和神经元细胞的细胞核，以及相应的内在防御， 大多数病原体都被隔离了我们包括初步数据表明，这种开创性的合作 这项研究具有深远的医学和生物学意义。