Establishing a Laboratory Model of Herpes simplex virus (HSV) Latency Using Compartmented Neuron Cultures

使用区室神经元培养物建立单纯疱疹病毒 (HSV) 潜伏期的实验室模型

基本信息

  • 批准号:
    9895176
  • 负责人:
  • 金额:
    $ 20.25万
  • 依托单位:
  • 依托单位国家:
    美国
  • 项目类别:
  • 财政年份:
    2020
  • 资助国家:
    美国
  • 起止时间:
    2020-01-15 至 2020-12-31
  • 项目状态:
    已结题

项目摘要

Alpha herpesvirus infections (e.g. herpes simplex virus 1 and 2; HSV-1 and HSV-2) are among the most common virus infections in the world affecting more than 70% of human population. A typical alpha herpesvirus infection results in life-long latency in the peripheral nervous system (PNS) ganglia. Latent viral genomes can reactivate to start a disseminated infection often leading to herpes blisters, genital lesions or keratitis. The primary infection starts with a productive infection in the epithelial cells of mucosal surfaces. After replication, progeny virus particles mainly invade the dorsal root and trigeminal ganglia (DRG and TG), and other autonomic sympathetic ganglia (e.g. SCG) to establish latency. Establishment of latency, reactivation, and subsequent spread of infection is affected by many cell intrinsic, tissue-specific and systemic factors that are challenging to dissect. The available anti-herpetic drugs target viral DNA replication but have no effect on latent or reactivating viral genomes. Consistent and reproducible laboratory models are required to dissect the molecular mechanisms of latency and reactivation to be able to design novel therapies. Currently used neuron culture models of HSV-1 latency employs dissociated rodent primary neurons with the use of acyclovir to inhibit DNA replication and force the infection into latency. This is not ideal, not only because the virions are directly infecting neuronal cell bodies instead of axons, but also because the viral DNA that incorporated the guanine analogue might not be competent for further replication. Recently, we have developed a reproducible and reactivatable in vitro latency system by infecting isolated axons of compartmented neurons with a low concentration of the veterinary pathogen, pseudorabies virus without the use of drugs. Since the outcome of infection is always silenced under these conditions, we studied mechanisms that enable escape from genome silencing. We discovered two distinct pathways that prevented PRV genome silencing. We will develop this system to explore the molecular mechanisms of latency establishment and reactivation of the human pathogen, HSV-1. Identification of neuronal stress pathways enabling escape from silencing will contribute to designing novel therapeutic strategies to control virus reactivation and related pathologies in patients with recurrent herpesvirus reactivation.
阿尔法疱疹病毒感染(例如单纯疱疹病毒1和2;单纯疱疹病毒1和单纯疱疹病毒2)是世界上最常见的病毒感染之一,影响70%以上的人口。典型的阿尔法疱疹病毒感染会导致周围神经系统(PNS)神经节的终生潜伏期。潜伏的病毒基因组可以重新激活,开始传播性感染,通常会导致疱疹、生殖器病变或角膜炎。原发感染始于粘膜表面上皮细胞的生产性感染。复制后,子代病毒颗粒主要侵入背根节和三叉神经节(DRG和TG)以及其他自主交感神经节(如SCG)以建立潜伏期。潜伏期的建立、重新激活和随后的感染扩散受到许多细胞固有的、组织特有的和系统性的因素的影响,这些因素很难剖析。现有的抗疱疹药物针对病毒DNA复制,但对潜伏或重新激活病毒基因组没有影响。需要一致和可重复的实验室模型来剖析潜伏期和再激活的分子机制,以便能够设计新的治疗方法。目前使用的HSV-1潜伏期神经元培养模型使用分离的啮齿动物原代神经元和阿昔洛韦来抑制DNA复制并迫使感染进入潜伏期。这并不理想,不仅是因为病毒粒子直接感染神经元细胞体,而不是轴突,还因为含有鸟嘌呤类似物的病毒DNA可能无法进一步复制。最近,我们在不使用药物的情况下,通过用低浓度的兽医病原体伪狂犬病病毒感染隔区神经元的分离轴突,开发了一种可重复和可再激活的体外潜伏期系统。由于感染的结果在这些条件下总是沉默的,我们研究了能够逃避基因组沉默的机制。我们发现了两条不同的途径来防止PRV基因组沉默。我们将开发这个系统来探索人类病原体HSV-1潜伏期建立和重新激活的分子机制。识别神经元应激途径使其能够逃避沉默,将有助于设计新的治疗策略来控制复发疱疹病毒再激活患者的病毒再激活和相关病理。

项目成果

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Orkide O. Koyuncu其他文献

Orkide O. Koyuncu的其他文献

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{{ truncateString('Orkide O. Koyuncu', 18)}}的其他基金

Establishing a Laboratory Model of Herpes simplex virus (HSV) Latency Using Compartmented Neuron Cultures
使用区室神经元培养物建立单纯疱疹病毒 (HSV) 潜伏期的实验室模型
  • 批准号:
    10326688
  • 财政年份:
    2020
  • 资助金额:
    $ 20.25万
  • 项目类别:

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