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.

自主神经和感觉神经元中HSV1和HSV2的应力激素调节 抽象的 HSV1和HSV2返回通常会导致皮肤病变，但也可能导致失明，骨脑膜炎或 威胁生命的脑炎。已知压力是HSV复发性疾病的主要触发因素之一 令人惊讶的是，它如何做到这一点。尽管大多数研究都集中在感官中的病毒潜伏期上 三叉神经节或腰椎背根神经节的神经元，HSV也建立了潜伏期 自主神经元对面部和生殖器的支配和生殖器有很大不同，对已知的反应很高 重新激活刺激，可能有助于HSV1和HSV2的差异发病机理。我们的初步研究 证明是自主神经系统的一个分支的同情途径具有 对HSV1急性疾病症状的严重程度的重大影响，造成HSV1的74％，49％ HSV2在体内返回。由自主神经系统调节的应力激素调节不同 神经元通过糖皮质激素和肾上腺素受体的类型，它们以不同的方式表达 HSV1和HSV2建立潜伏期的感觉和自主神经元。短期应力本人 肾上腺素诱导HSV1重新激活，但不能诱导HSV2，这仅发生在交感神经元中。相比之下， 皮质酮（皮质醇的啮齿动物形式，长期应力本）诱导HSV1和 HSV2。但是，皮质酮导致HSV1仅在交感神经元中重新激活，但导致HSV2为 在交感神经和感觉神经元中重新激活。我们已经确定了肾上腺素的受体 皮质酮影响重新激活，并具有大量的初步数据，提示特定信号传导 参与重新激活过程的途径和蛋白质。该提议的中心假设 是应力激素选择性调节自主神经元中的HSV1和HSV2感染，导致 HSV1和HSV2的差异激活和复发频率。使用原发性成人神经元培养 和豚鼠感染模型，我们将1）确定肾上腺素的信号传导途径 有选择地诱导原发性成人交感神经元的HSV1重新激活，2）确定信号传导 皮质酮（Cort）选择性诱导HSV1和HSV2重新激活的途径 成人感觉和交感神经元。拟议的研究预计将挑战HSV的范式 通过证明延迟的维持和重新激活过程不是“一种尺寸适合所有人”来重新激活， 自主神经元是HSV复发性疾病的重要来源。我们的研究将表明不同 机理在不同类型的神经元中引起HSV1和HSV2的重新激活。这项工作也有深远的角度 了解感官和自主神经元如何对病毒感染的反应不同，在 一般的。