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: 10566262
• 负责人: Andrea S Bertke
• 金额: $ 37.91万
• 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/10566262
• 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; Genetic Transcription; 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; Trigeminal System; VP 16; Virus; Virus Diseases; Virus Latency; Work; antiviral drug development; disease transmission; 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的复发通常会导致皮肤损害，但也可能导致失明、骶部脑膜炎或 危及生命的脑炎。众所周知，应激是HSV复发的主要诱因之一，尽管 令人惊讶的是，人们对它是如何做到这一点知之甚少。尽管大多数研究都集中在感官上的病毒潜伏期 三叉神经节或腰骶背根神经节的神经元，单纯疱疹病毒也建立潜伏期 自主神经支配面部和生殖器的方式截然不同，它对已知的 重新激活刺激，并可能有助于HSV1和HSV2的不同发病机制。我们的初步研究 证明交感神经通路，这是自主神经系统的一个分支，具有 对HSV1急性疾病症状的严重程度产生重大影响，并导致74%的HSV1和49%的HSV1 HSV2在体内复发。应激激素，由自主神经系统调节，调节不同的 通过糖皮质激素和肾上腺素能受体的神经元类型，这两种受体在 在HSV1和HSV2中建立潜伏期的感觉神经元和自主神经元。短期应激激素 肾上腺素可诱导HSV1重新激活，但不能激活HSV2，而且这种激活只发生在交感神经元中。相比之下， 皮质酮(啮齿类皮质醇，长期应激激素)诱导HSV1和HSV1重新激活 HSV2。然而，皮质酮只导致HSV1在交感神经元重新激活，但导致HSV2在交感神经元重新激活 交感神经元和感觉神经元都重新激活。我们已经确定了肾上腺素通过哪些受体 和皮质酮诱导重新激活，并有大量的初步数据表明特定的信号 参与重新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HSV1和HSV2的感染，导致 HSV1和HSV2的激活和复发频率不同。使用原代培养的成人神经元 以及豚鼠感染模型，我们将1)确定肾上腺素通过哪些信号通路 选择性地从初级成人交感神经元中诱导HSV1重新激活，以及2)识别信号 皮质酮(CORT)选择性诱导HSV1和HSV2重新激活的途径 成人感觉神经元和交感神经元。这项拟议的研究有望挑战单纯疱疹病毒的范式 通过证明潜伏期的维持和重新激活的过程不是“一刀切”， 自主神经是HSV复发疾病的重要来源。我们的研究将表明，不同的 机制导致HSV1和HSV2在不同类型的神经元中重新激活。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如何对病毒感染做出不同反应的启示 将军。