Role of receptor-interacting serine/threonine-protein kinase 3 (RIPK3) in Herpes Simplex Virus (HSV) Encephalitis

受体相互作用丝氨酸/苏氨酸蛋白激酶 3 (RIPK3) 在单纯疱疹病毒 (HSV) 脑炎中的作用

基本信息

批准号：
10645451
负责人：
Hongyan Guo
金额：
$ 21.9万
依托单位：
LOUISIANA STATE UNIV HSC SHREVEPORT
依托单位国家：
美国
项目类别：
财政年份：
2023
资助国家：
美国
起止时间：
2023-02-15 至 2025-01-31
项目状态：
未结题

来源：
https://reporter.nih.gov/project-details/10645451
关键词：
Apoptosis Apoptotic Brain C57BL/6 Mouse CASP8 gene Cell Death Cell Separation Cells Central Nervous System Cessation of life Collaborations Complex Cytoplasm Development Diagnosis Disease Double Stranded DNA Virus Encephalitis Functional disorder Herpes Simplex Infections Herpes encephalitis Herpesvirus 1 Human Immune response In Vitro Infection Inflammation Inflammatory Innate Immune Response Interleukin-1 beta Invaded Knock-in Knowledge Left Life Literature Mediating Mediator Microglia Modeling Mus Necrosis Outcome Pathogenesis Pathology Pathway interactions Performance Persons Phosphotransferases Prevalence Production Public Health RIPK3 gene Regulation Research Role Signal Transduction Supporting Cell Testing Therapeutic Viral Virus Virus Diseases Virus Replication Western World adaptive immune response attenuation chemokine cytokine improved in vivo mortality mouse model neuroinflammation novel therapeutic intervention novel therapeutics prevent scaffold therapeutic target

项目摘要

This project, “Role of receptor-interacting serine/threonine-protein kinase 3 (RIPK3) in Herpes Simplex Virus (HSV) Encephalitis”, aims to define the precise contribution of RIPK3 to Herpes Simplex Virus (HSV)-1 pathogenesis by using the experimental Herpes Simplex Encephalitis (HSE) model. We have found that RIPK3 kinase-dependent necroptosis restricts HSV-1 replication in human cells as well as mouse cells. The attenuation of HSV-1 propagation in mice was attributed to RIPK3-mediated necroptosis in current literature. Little information is available about the precise contribution of RIPK3 toward onset and development of the life- threatening virus-induced encephalitis. Using a well-accepted mouse model of HSE and unique knock-in/out mice, we have now obtained new evidence suggesting that RIPK3 restricts HSV-1-induced encephalitis via a RIPK3-necroptosis independent scaffolding function in the central nervous system (CNS), which requires caspase 8 function. The mechanism through which RIPK3 collaborates with caspase 8 to restrict HSE will be determined over the course of the project. Two complementary and interrelated research directions will be pursued. Specific Aim 1 will test the hypothesis that HSV1 infection drives RIPK3 activation of caspase 8- mediated apoptosis in microglia to restrict pathogenesis of HSV1-induced encephalitis. Specific Aim 2 will test the hypothesis that RIPK3 scaffolding function coordinates protective neuroinflammation and dictates antiviral immune response to restrict pathogenesis of HSV1-induced encephalitis. Ultimately, we expect to (1) establish that RIPK3 scaffolding function, by collaborating with caspase 8, is important for HSE restriction rather than the kinase activity, and (2) show that RIPK3 regulates brain inflammation via stimulation of key proinflammatory cytokines/chemokines. The studies proposed herein are intended to fill a major existing knowledge gap in our understanding of the RIPK3 and the pathogenesis of HSE. The impact on the field of HSE will include establishing fundamental mechanisms of targeting RIPK3 signaling therapeutically towards diagnosing, preventing, and/or treating this life-threatening virus-induced encephalitis in human settings.

该项目“受体相互作用丝氨酸/苏氨酸蛋白激酶 3 (RIPK3) 在单纯疱疹病毒中的作用” (HSV) 脑炎”，旨在明确 RIPK3 对单纯疱疹病毒 (HSV)-1 的精确贡献通过使用实验性单纯疱疹脑炎（HSE）模型，我们发现了 RIPK3 的发病机制。激酶依赖性坏死性凋亡限制 HSV-1 在人类细胞和小鼠细胞中的复制。在目前的文献中，HSV-1 在小鼠体内的传播归因于 RIPK3 介导的坏死性凋亡。关于 RIPK3 对生命的发生和发展的精确贡献的信息是可用的。使用广为接受的 HSE 小鼠模型和独特的敲入/敲除技术。小鼠中，我们现在获得了新的证据表明 RIPK3 通过以下方式限制 HSV-1 诱导的脑炎： RIPK3-中枢神经系统（CNS）中坏死性凋亡独立的支架功能，这需要 caspase 8 的功能。RIPK3 与 caspase 8 合作限制 HSE 的机制是在该项目的过程中将确定两个互补且相互关联的研究方向。具体目标 1 将检验 HSV1 感染驱动 RIPK3 激活 caspase 8- 的假设。介导小胶质细胞凋亡以限制 HSV1 诱导的脑炎的发病机制将进行测试。 RIPK3 支架功能协调保护性神经炎症并决定抗病毒药物的假设最终，我们期望 (1) 建立免疫反应来限制 HSV1 诱导的脑炎的发病机制。 RIPK3 支架功能通过与 caspase 8 合作，对于 HSE 限制而不是激酶活性，(2) 表明 RIPK3 通过刺激关键的促炎症因子来调节脑炎症本文提出的研究旨在填补我们现有的主要知识空白。对 RIPK3 和 HSE 发病机制的了解对 HSE 领域的影响将包括建立以 RIPK3 治疗为诊断目标的基本机制，在人类环境中预防和/或治疗这种危及生命的病毒引起的脑炎。