Neuron Specific Regulation of HSV1 and HSV2 Outcomes of Infection

HSV1和HSV2感染结局的神经元特异性调节 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以产生不同的 裂解、潜伏或重新激活感染的结果。众所周知，单纯疱疹病毒(HSV1和 HSV2)在感觉神经元和自主神经中建立潜伏期，从潜伏期开始它们可以重新激活以导致复发 疾病。然而，一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重新激活，但仅来自 这些潜伏感染的神经元。支持这些不同结果的神经元群体在以下方面有所不同 HSV1和HSV2导致不同的解剖模式和复发频率。充分地 了解成熟的感觉神经元如何允许或抑制病毒复制，研究这些是至关重要的 适当的神经元中的机制。我们已经确定，在成人的感觉神经元中， 胶质细胞源性神经营养因子(GDNF)和神经突蛋白(NTN)通过 它们的受体是GFR1和GFR2。剥夺GDNF或NTN选择性地诱导HSV2或HSV1 重新激活。GFR1/2信号通过RET激活几个下游信号通路以维持 细胞功能，还维持与病毒基因组特定区域结合的蛋白质的存在。 这一提议的中心假设是GDNF和NTN通过RET不断地发出信号以 在成年感觉神经元中保持HSV1和HSV2的潜伏状态。此外，连续信令 在病毒基因组上沉积抑制性神经元蛋白，包括染色质修饰 与不活跃的基因转录有关。利用我们创新的原代成人感觉神经元培养， 结合总结不同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)决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不同地诱导HSV1和HSV2重新激活。这个 推动这一项目的基本原理是，通过识别神经因素和机制，自然地防止 在特定类型的神经元中复制和重新激活HSV，我们可以识别靶向神经元通路和 在任何类型的神经元中，将病毒永久锁定在无法重新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.