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

该项目，“受体相互作用丝氨酸/苏氨酸蛋白激酶3（RIPK 3）在单纯疱疹病毒中的作用” (HSV)Encephaly”，旨在确定RIPK 3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病毒脑炎（HSE）模型研究其发病机制。我们发现RIPK 3 激酶依赖性坏死性凋亡限制了HSV-1在人细胞以及小鼠细胞中的复制。衰减 在目前的文献中，HSV-1在小鼠中的传播归因于RIPK 3介导的坏死性凋亡。小 关于RIPK 3对生命发生和发展的精确贡献的信息是可用的， 威胁病毒引起的脑炎使用广泛接受的HSE小鼠模型和独特的敲入/敲出 在小鼠中，我们现在已经获得了新的证据，表明RIPK 3通过抑制HSV-1诱导的脑炎， RIPK 3-中枢神经系统（CNS）中的坏死性凋亡独立支架功能，这需要 caspase 8功能。RIPK 3与caspase 8合作限制HSE的机制将是 在项目的过程中确定。两个相互补充和相互关联的研究方向将是 追求。特异性目的1将检验HSV 1感染驱动caspase 8的RIPK 3活化的假设。 介导的小胶质细胞凋亡，以限制HSV 1诱导的脑炎的发病机制。第2章测试 RIPK 3支架功能协调保护性神经炎症并决定抗病毒的假设 限制HSV 1诱导脑炎发病机制的免疫应答。最终，我们希望（1）建立 RIPK 3支架功能，通过与caspase 8合作，对HSE限制很重要，而不是 激酶活性，以及（2）显示RIPK 3通过刺激关键的促炎性蛋白激酶来调节脑炎症。 细胞因子/趋化因子。本文提出的研究旨在填补我们现有的一个主要知识空白， 了解RIPK 3和HSE的发病机制。对HSE领域的影响将包括 建立以RIPK 3信号传导为靶点的治疗性诊断的基本机制， 在人类环境中预防和/或治疗这种威胁生命的病毒诱导的脑炎。

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.