Neuron Specific Regulation of HSV1 and HSV2 Outcomes of Infection

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时支持HSV复制，而其他类型的神经元在进入时支持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。使用我们创新的原代成人感觉神经元培养物， 结合体内模型，重现不同的HSV 1和HSV 2复发模式，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。

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.