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：
9912871
负责人：
Andrea S Bertke
金额：
$ 34.04万
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 2023-04-30
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/9912871
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 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.

HSV1 和 HSV2 感染结果的神经元特异性调节抽象的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以产生不同的病毒感染众所周知，单纯疱疹病毒（HSV1 和 HSV1）是溶解性、潜伏性或再激活性感染的结果。 HSV2）在感觉和自主神经元中建立潜伏期，从中它们可以重新激活以引起复发然而，某些类型的神经元在进入时支持 HSV 复制，而其他类型则自然支持。抑制病毒复制，导致潜伏期外源刺激可以触发重新激活，但仅限于一部分。这些潜伏感染的神经元支持这些不同的结果。 HSV1 和 HSV2，导致不同的解剖模式和复发性疾病的频率。成熟的感觉神经元如何允许或抑制病毒复制，有必要研究这些我们已经确定，在成人感觉神经元中，连续的机制。胶质细胞源性神经营养因子 (GDNF) 和神经营养因子 (NTN) 的存在通过维持 HSV 潜伏期它们的受体 GFRα1 和 GFRα2 剥夺 GDNF 或 NTN 选择性诱导 HSV2 或 HSV1。 GFRα1/2 信号通过 RET 激活多个下游信号通路以维持细胞功能，并且还维持与病毒基因组特定区域结合的蛋白质的存在。该提案的中心假设是 GDNF 和 NTN 通过 RET 不断发出信号维持成人感觉神经元中 HSV1 和 HSV2 的潜伏状态。此外，持续信号传导。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相关，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 HSV1 和 HSV2 复发模式的体内模型，我们将 1) 确定神经营养因子调节 HSV1 和 HSV2 的神经信号通路感染，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差异诱导体内 HSV1 和 HSV2 重新激活。推动该项目的基本原理是，通过识别自然预防的神经因素和机制 HSV 在特定类型的神经元中复制和重新激活，我们可以识别可靶向的神经元通路并在任何类型的神经元中将病毒永久锁定为无法重新激活的潜伏状态的因素。