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

基本信息

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
项目类别：
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

项目摘要

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 的应激激素调节抽象的 HSV1 和 HSV2 复发通常会导致皮肤损伤，但也可能导致失明、骶骨脑膜炎或已知压力是危及生命的脑炎是 HSV 复发的主要诱因之一。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觉上的病毒潜伏期。 HSV 在三叉神经节或腰骶背根神经节的神经元中也建立潜伏期自主神经元以非常不同的方式支配面部和生殖器，对已知的神经元高度敏感再激活刺激，可能有助于 HSV1 和 HSV2 的不同发病机制。证明交感神经通路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有显着影响，占 HSV1 的 74% 和 49% HSV2 在体内复发，受自主神经系统调节，调节不同的应激激素。通过糖皮质激素和肾上腺素能受体来识别神经元类型，这些受体以不同的模式表达感觉和自主神经元，其中 HSV1 和 HSV2 建立潜伏期的短期应激激素。肾上腺素会诱导 HSV1 重新激活，但不会诱导 HSV2 重新激活，而且这只发生在交感神经元中。皮质酮（皮质醇的啮齿动物形式，长期应激激素）会诱导 HSV1 和 HSV1 的重新激活 HSV2 然而，皮质酮仅导致 HSV1 在交感神经元中重新激活，但会导致 HSV2 我们已经确定了肾上腺素通过的受体重新激活。和皮质酮诱导再激活，并有大量初步数据表明特定信号传导该提案的中心假设是参与重新激活过程的途径和蛋白质。应激激素选择性调节自主神经元中的 HSV1 和 HSV2 感染，从而导致使用原代成人神经元培养物观察 HSV1 和 HSV2 的不同再激活和复发频率。和豚鼠感染模型，我们将 1) 确定肾上腺素通过的信号通路选择性诱导初级成体交感神经元的 HSV1 重新激活，2) 识别信号传导皮质酮 (CORT) 选择性诱导原发性 HSV1 和 HSV2 重新激活的途径成人感觉和交感神经元的研究有望挑战 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”来重新激活，我们的研究表明，自主神经元是 HSV 复发性疾病的重要来源。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影响。对于理解感觉神经元和自主神经元如何对病毒感染做出不同反应的影响一般的。