Stress Hormone Regulation of HSV1 and HSV2 in Autonomic and Sensory Neurons

自主神经和感觉神经元中 HSV1 和 HSV2 的应激激素调节

• 批准号: 10708144
• 负责人: Andrea S Bertke
• 金额: $ 38.63万
• 依托单位: VIRGINIA POLYTECHNIC INST AND ST UNIV
• 依托单位国家: 美国
• 财政年份: 2022
• 资助国家: 美国
• 起止时间: 2022-09-21 至 2027-08-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10708144
• 关键词: Acute Disease; Adrenergic Receptor; Adult; Afferent Neurons; Animal Model; Antiviral Agents; Autonomic Pathways; Autonomic nervous system; Blindness; CREB1 gene; Cavia; Chromatin; Corticosterone; Cyclic AMP; Data; Development; Encephalitis; Epinephrine; Event; Face; Frequencies; GTP-Binding Protein alpha Subunits; Genital; Genitalia; Glucocorticoid Receptor; Goals; Herpesvirus 1; Hormones; Human Herpesvirus 2; Hydrocortisone; Infection; Interferons; Life; MAPK8 gene; Maintenance; Mediating; Meningitis; Mineralocorticoid Receptor; Modeling; Neurons; Organ; Pathogenesis; Pathway interactions; Pattern; Pelvis; Process; Recurrence; Recurrent disease; Research; Rodent; Sensory; Severities; Signal Pathway; Signaling Protein; Simplexvirus; Source; Spinal Ganglia; Stimulus; Stress; Structure of trigeminal ganglion; Symptoms; Transcription Initiation; Trigeminal System; VP 16; Virus; Virus Activation; Virus Diseases; Virus Latency; Work; antiviral drug development; experimental study; hormone regulation; human model; in vivo; innovation; prevent; receptor; response; skin lesion; transmission process; viral DNA

Stress Hormone Regulation of HSV1 and HSV2 in Autonomic and Sensory Neurons Abstract HSV1 and HSV2 recurrences typically result in skin lesions but may also cause blindness, sacral meningitis, or life-threatening encephalitis. Stress is known to be one of the primary triggers for HSV recurrent disease, although surprisingly little is known about how it does so. Although most studies have focused on viral latency in sensory neurons of either the trigeminal ganglia or lumbosacral dorsal root ganglia, HSV also establishes latency in autonomic neurons, which innervate the face and genitals very differently, are highly responsive to known reactivation stimuli, and likely contribute to differential pathogenesis of HSV1 and HSV2. Our preliminary studies demonstrate that the sympathetic pathways, which are one branch of the autonomic nervous system, have a significant impact on the severity of HSV1 acute disease symptoms and contribute to 74% of HSV1 and 49% of HSV2 recurrences in vivo. Stress hormones, regulated by the autonomic nervous system, modulate different types of neurons through glucocorticoid and adrenergic receptors, which are expressed in different patterns on sensory and autonomic neurons in which HSV1 and HSV2 establish latency. The short-term stress hormone epinephrine induces HSV1 reactivation, but not HSV2, and this only occurs in sympathetic neurons. In contrast, corticosterone (the rodent form of cortisol, the long-term stress hormone) induces reactivation of both HSV1 and HSV2. However, corticosterone cause HSV1 to reactivate only in sympathetic neurons, but causes HSV2 to reactivate in both sympathetic and sensory neurons. We have identified the receptors through which epinephrine and corticosterone induce reactivation and have substantial preliminary data suggesting specific signaling pathways and proteins that are involved in the process of reactivation. The central hypothesis of this proposal is that stress hormones selectively regulate HSV1 and HSV2 infections in autonomic neurons, leading to differential reactivation and recurrence frequencies of HSV1 and HSV2. Using primary adult neuronal cultures and the guinea pig infection model, we will 1) identify the signaling pathways through which epinephrine selectively induces HSV1 reactivation from primary adult sympathetic neurons, and 2) identify the signaling pathways through which corticosterone (CORT) selectively induces HSV1 and HSV2 reactivation from primary adult sensory and sympathetic neurons. The proposed research is expected to challenge the paradigm of HSV reactivation by demonstrating that maintenance of latency and the process of reactivation are not “one size fits all,” and that autonomic neurons are an important source of HSV recurrent disease. Our studies will show that different mechanisms cause reactivation of HSV1 and HSV2 in different types of neurons. The work also has far-reaching implications for understanding how sensory and autonomic neurons differentially respond to viral infections, in general.

HSV1和HSV2在自主神经元和感觉神经元中的应激激素调节 摘要 HSV1和HSV2复发通常导致皮肤损伤，但也可能导致失明、骶骨脑膜炎或其他疾病。 危及生命的脑炎已知压力是HSV复发性疾病的主要诱因之一，尽管 令人惊讶的是，人们对它是如何做到这一点的知之甚少。尽管大多数研究都集中在感觉神经系统中的病毒潜伏期， 在三叉神经节或腰骶部背根神经节的神经元中，HSV也建立潜伏期， 自主神经元对面部和生殖器的神经支配非常不同，它们对已知的神经元高度敏感。 激活刺激，并可能有助于HSV 1和HSV 2的不同发病机制。我们的初步研究 证明交感神经通路，这是一个分支的自主神经系统，有一个 对HSV 1急性疾病症状的严重程度有显著影响，并导致74%的HSV 1和49%的 HSV 2在体内复发。由自主神经系统调节的应激激素调节不同的 通过糖皮质激素和肾上腺素能受体，这是在不同的模式上表达的神经元类型。 感觉和自主神经元，其中HSV 1和HSV 2建立潜伏期。短期应激激素 肾上腺素诱导HSV 1再激活，但不诱导HSV 2，并且这仅发生在交感神经元中。与此相反， 皮质酮（啮齿类动物形式的皮质醇，长期应激激素）诱导HSV 1和HSV 2的重新激活。 HSV 2型。然而，皮质酮仅在交感神经元中引起HSV 1重新激活，而在交感神经元中引起HSV 2重新激活。 在交感神经元和感觉神经元中重新激活。我们已经确定了肾上腺素 和皮质酮诱导再激活，并有大量的初步数据表明， 参与再激活过程的途径和蛋白质。这项提议的核心假设是 应激激素选择性地调节自主神经元中的HSV 1和HSV 2感染， HSV1和HSV2的不同再激活和复发频率。使用原代成人神经元培养物 和豚鼠感染模型，我们将1）确定肾上腺素通过哪些信号通路 选择性地诱导HSV 1从原代成人交感神经元再激活，和2）鉴定信号传导 皮质酮（CORT）选择性诱导HSV 1和HSV 2从原发性 成年感觉和交感神经元。这项拟议中的研究有望挑战HSV的范式 通过证明延迟的维持和重新激活的过程不是“一刀切”， 自主神经元是HSV复发的重要来源。我们的研究表明， 这些机制导致HSV 1和HSV 2在不同类型的神经元中的再激活。这项工作也具有深远的意义 对理解感觉神经元和自主神经元对病毒感染的不同反应的影响， 将军