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Neuron Specific Regulation of HSV1 and HSV2 Outcomes of Infection

HSV1 和 HSV2 感染结果的神经元特异性调节

基本信息

批准号：
10391469
负责人：
Andrea S Bertke
金额：
$ 33.94万
依托单位：
VIRGINIA POLYTECHNIC INST AND ST UNIV
依托单位国家：
美国
项目类别：
财政年份：
2018
资助国家：
美国
起止时间：
2018-06-15 至 2024-04-30
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/10391469
关键词：
AKT Signaling Pathway Acute Disease Adult Affect Afferent Neurons Anatomy Antiviral Agents Binding Proteins Cavia Cell Differentiation process Cell Line Cell physiology Clinical Deposition Development Disease Embryo Epigenetic Process Event Frequencies Gene Silencing Genetic Transcription Goals Herpesvirus 1 Heterochromatin Human Herpesvirus 2 Infection Knowledge Lytic Maintenance Modeling Mus Nerve Growth Factors Neuroglia Neurons Neurovirology Oryctolagus cuniculus Outcome Pathogenesis Pathway interactions Pattern Periodicity Persons Population Process Proteins Proteomics Recurrence Recurrent disease Regulation Research Sensory Signal Pathway Signal Transduction Simplexvirus Specificity Stimulus Testing Tissues Viral Genome Virus Virus Diseases Virus Replication Virus Shedding base chromatin modification deprivation disease transmission experience improved in vivo in vivo Model innovation neurotransmission neurotrophic factor neurturin prevent receptor transcriptome sequencing transmission process

项目摘要

Neuron Specific Regulation of HSV1 and HSV2 Outcomes of Infection Abstract Our overall goal is to identify how different types of neurons regulate viral infections to produce divergent outcomes of lytic, latent or reactivating infections. It is well-established that herpes simplex viruses (HSV1 and HSV2) establish latency in sensory and autonomic neurons, from which they can reactivate to cause recurrent disease. However, some types of neurons support HSV replication upon entry, while other types naturally inhibit viral replication, resulting in latency. Exogenous stimuli can trigger reactivation, but only from a portion of these latently infected neurons. The neuronal populations that support these divergent outcomes differ for HSV1 and HSV2, leading to different anatomical patterns and frequencies of recurrent disease. To fully understand how mature sensory neurons permit or inhibit viral replication, it is essential to study these mechanisms in the appropriate neurons. We have determined that in adult sensory neurons, continuous presence of glial cell derived neurotrophic factor (GDNF) and neurturin (NTN) maintain HSV latency through their receptors, GFR1 and GFR2. Deprivation of GDNF or NTN selectively induces HSV2 or HSV1 reactivation. GFR1/2 signaling through RET activates several downstream signaling pathways to maintain cellular function, and also maintains the presence of proteins bound to specific regions of the viral genome. The central hypothesis of this proposal is that that GDNF and NTN continuously signal through RET to maintain HSV1 and HSV2 in a latent state in adult sensory neurons. Furthermore, continuous signaling deposits inhibitory neuronal proteins onto the viral genome, including chromatin modifications associated with inactive gene transcription. Using our innovative primary adult sensory neuronal cultures, combined with an in vivo model that recapitulates the different HSV1 and HSV2 recurrence patterns, we will 1) identify the neuronal signaling pathways through which neurotrophic factors regulate HSV1 and HSV2 infections, 2) determine how neurotrophic factors maintain the latent state of the viral genome, and 3) determine how neurotrophic factor deprivation differentially induces HSV1 and HSV2 reactivation in vivo. The rationale that drives this project is that by identifying neuronal factors and mechanisms that naturally prevent HSV replication and reactivation in specific types of neurons, we can identify targetable neuronal pathways and factors to permanently lock the virus into a latent state incapable of reactivation, in any type of neuron.

神经元特异性调控HSV 1和HSV 2感染结局摘要我们的总体目标是确定不同类型的神经元如何调节病毒感染，溶解性、潜伏性或再激活性感染的结果。已经确定，单纯疱疹病毒（HSV 1和HSV 2）可以通过多种途径感染人类。 HSV-2）在感觉和自主神经元中建立潜伏期，它们可以从中重新激活以引起复发性疾病然而，某些类型的神经元在进入后支持HSV复制，而其他类型的神经元则自然地支持HSV复制抑制病毒复制，导致潜伏期。外源性刺激可以触发再激活，但仅来自一部分这些潜伏感染的神经元。支持这些不同结果的神经元群体对于 HSV 1和HSV 2，导致不同的解剖模式和复发疾病的频率。充分为了了解成熟的感觉神经元如何允许或抑制病毒复制，研究这些神经元是至关重要的。在适当的神经元机制。我们已经确定，在成年感觉神经元中，胶质细胞源性神经营养因子（GDNF）和neurturin（NTN）的存在维持HSV潜伏期，它们的受体GFR α 1和GFR α 2。GDNF或NTN的去磷酸化选择性诱导HSV 2或HSV 1 重新激活通过RET的GFR β 1/2信号传导激活几个下游信号传导通路，以维持细胞功能，并且还维持与病毒基因组的特定区域结合的蛋白质的存在。这一建议的中心假设是GDNF和NTN通过RET持续发信号，维持HSV 1和HSV 2在成年感觉神经元中处于潜伏状态。此外，连续信号将抑制性神经元蛋白沉积到病毒基因组上，包括染色质修饰与不活跃的基因转录有关。使用我们创新的初级成人感觉神经元培养物，结合概括不同HSV 1和HSV 2复发模式的体内模型，我们将1）确定神经营养因子调节HSV 1和HSV 2的神经元信号通路感染，2）确定神经营养因子如何维持病毒基因组的潜伏状态，以及3）确定神经营养因子剥夺如何在体内差异诱导HSV 1和HSV 2再激活。的推动这个项目的基本原理是，通过识别神经元因素和机制， HSV在特定类型的神经元中的复制和再激活，我们可以识别靶向神经元通路，在任何类型的神经元中，永久锁定病毒进入无法再激活的潜伏状态的因素。

项目成果

期刊论文数量（8）

专著数量（0）

科研奖励数量（0）

会议论文数量（0）

专利数量（0）

Neurotrophic Factors NGF, GDNF and NTN Selectively Modulate HSV1 and HSV2 Lytic Infection and Reactivation in Primary Adult Sensory and Autonomic Neurons.

神经营养因子 NGF、GDNF 和 NTN 选择性调节初级成人感觉和自主神经元中的 HSV1 和 HSV2 溶解感染和再激活。

DOI：
10.3390/pathogens6010005
发表时间：
2017
期刊：
Pathogens (Basel, Switzerland)
影响因子：
0
作者：
Yanez,AndyA;Harrell,Telvin;Sriranganathan,HeatherJ;Ives,AngelaM;Bertke,AndreaS
通讯作者：
Bertke,AndreaS

Herpes Simplex Virus 1 (HSV-1) Infected Cell Protein 0 (ICP0) Targets of Ubiquitination during Productive Infection of Primary Adult Sensory Neurons.