Stress-Mediated Regulation of HSV-1 Reactivation from Latency

应激介导的 HSV-1 潜伏期再激活调节

基本信息

批准号：
10331857
负责人：
CLINTON J JONES
金额：
$ 35.16万
依托单位：
OKLAHOMA STATE UNIVERSITY STILLWATER
依托单位国家：
美国
项目类别：
财政年份：
2020
资助国家：
美国
起止时间：
2020-04-01 至 2025-01-31
项目状态：
未结题

来源：
https://reporter.nih.gov/project-details/10331857
关键词：
Address Adrenal Cortex Hormones Alzheimer&apos s Disease Axon Binding Brain Stem ChIP-seq Chronic stress Complex Dexamethasone Disease Early Promoters Encephalitis Eye Infections Eye diseases Frequencies Gene Expression Genes Genetic Transcription Genomics Glucocorticoid Receptor Health Herpesvirus 1 Human Immune Incidence Incubated Infection Knockout Mice Kruppel-like transcription factors Lead Life Lytic Phase Maintenance Mediating Metabolic Microarray Analysis Modeling Molecular Mucous Membrane Mus Mutant Strains Mice Neurons Pathway interactions Physiological Production Promoter Regions Proteins Publishing Receptor Activation Recurrence Recurrent disease Regulation Research Design Signal Pathway Stimulus Stress Structure of trigeminal ganglion Surface Testing VP 16 Viral Viral Genes Viral Regulatory Proteins Virus Virus Shedding Wild Type Mouse acute infection acute stress antagonist base beta catenin differential expression glucocorticoid receptor alpha human pathogen innovation insight latency associated transcript latent infection mutant neuronal survival promoter protein activation protein expression psychologic reactivation from latency repaired stressor transcription factor viral transmission

项目摘要

Project Summary & Abstract Herpes simplex virus 1 (HSV-1), an important human pathogen, establishes life-long latency in neurons within trigeminal ganglia (TG) and CNS, including brainstem. External stressors periodically trigger reactivation from latency, resulting in recurrent ocular disease and encephalitis. The synthetic corticosteroid dexamethasone significantly enhances reactivation from latency in HSV-1 latently infected mice. Conversely, a glucocorticoid receptor (GR) antagonist significantly reduces reactivation from latency. A transcription factor activated by the Wnt pathway, b-catenin, is expressed in more TG neurons during latency relative to stress induced reactivation suggesting b-catenin maintains latency. GR and a stress induced transcription factor, Krüppel like transcription factor 15 (KLF15), form a feed forward loop that synergistically transactivates viral immediate early promoters required for productive infection. Based on these exciting unpublished studies, we hypothesize that stress, via GR activation, has multi-pronged effects on the latency-reactivation cycle. An important early step during reactivation is a stressful stimulus disrupts latency by suppressing the canonical Wnt/b- catenin signaling pathway. A second early step is GR and KLF15 cooperatively stimulate viral gene expression, ultimately leading to virus production. Studies in this proposal will directly test this hypothesis. For Aim 1, HSV-1 reactivation from latency will be compared in mice that do not express GR in TG or KLF15 knockout mice relative to wild-type mice. For Aim 2, we will investigate how GR and KLF15 synergistically activate viral transcription. Finally, differentially expressed genes associated with the Wnt/b-catenin signaling pathway will be identified during latency and reactivation from latency (Aim 3). Completion of these studies will reveal how stress disrupts latency and directly stimulates viral gene expression. !

项目摘要和摘要疱疹单纯疱疹病毒1（HSV-1），一种重要的人类病原体，建立了终身三叉神经节（TG）和中枢神经系统中神经元的潜伏期，脑干不可能。外部压力源周期性触发延迟重新激活，导致复发眼部疾病和脑炎。 HSV-1潜伏期感染的小鼠的潜伏期重新激活。相反，糖皮质激素受体（GR）拮抗剂显着降低了重新激活从延迟。相对于应力诱导的重新激活，在潜伏期中更多的TG神经元中表达提示B-cateninimaintains延迟和应力引起的转录因子 Krüppel喜欢转录因子15（KLF15），形成一个feed向前循环，该循环是协同作用基于生产感染所需的病毒立即激活。关于令人兴奋的未发表的研究，我们假设通过GR激活的压力具有对潜伏期反应周期的多种影响。重新激活是通过抑制规范的Wnt/b-来破坏潜伏期的 Cateninininaling途径是GRR和KLF15合作刺激病毒基因表达，最终导致病毒产生提案将直接检验该假设的目标1。在不表达GRRF15基因敲除小鼠的小鼠中进行比较野生型小鼠，我们将研究GR和KLF15 激活病毒转录。在潜伏期和重新激活期间，将确定Wnt/B-catenining途径潜伏期（目标3）。直接刺激病毒基因表达。呢