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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.

应激激素对HSV1和HSV2在自主和感觉神经元中的调节作用