LIGHT调节天然免疫促进神经节HSV-1增殖的细胞和分子学机制研究

Human herpes simplex virus-1(HSV-1) infects epithelial and mucosal cells then establishes life-long latent infection in host ganglia neurons. Although HSV-1 primary/latent / recurrent infections have been studied for half century, the virology mechanism remains unclear. In addition to intrinsic anti-viral activity of the infected cells, host immune regulation also plays a key role in outcomes of viral infection. During acute HSV-1 infection, innate immune response is activated first to control viral replication from primary infection, until adaptive immune response eventually clears viruses. However our recent study showed that LIGHT，as an inflammatory signaling， promotes HSV-1 replication and dissemination in mouse models. This phenomenon prompts an undiscovered mechanism of innate immune regulation and viral-host interaction. In this study, using a set of gene knockout mice in LIGHT signaling pathway, we will investigate the cellular and molecular mechanisms of LIGHT in regulating immune reponse against HSV-1 infection by exploring correlations among HSV-1infection, LIGHT signaling, and innate immune response. Our study will reveal the mechanism of LIGHT mediated immune regulation against HSV-1 proliferative and latent infection in nervous system and provide a critial guaidance for prevention and treatment of HSV-1 related diseases.

人类I-型单纯疱疹病毒 (HSV-1）感染上皮和粘膜组织继而在宿主的神经元建立终生潜伏感染。尽管对HSV-1感染/潜伏/复发这个饶有兴趣的问题已经进行了半个世纪的研究，其机制仍然很不清楚。病毒与宿主细胞的相互作用和机体的免疫调节对病毒感染的结局起着关键作用。HSV-1急性感染期，天然免疫应答首先被激活并控制原发感染的病毒复制，直至适应性免疫应答活化最终清除活动性感染。我们最近的一项研究结果证明天然免疫LIGHT信号通路能够促进HSV-1在小鼠神经组织内增殖和传播，此现象提示一个尚未被发现的免疫调节机制和潜在的病毒学机理。本研究中，我们拟利用LIGHT 和其受体LTβR 的基因敲除小鼠或嵌合体小鼠，探讨HSV-1感染、LIGHT信号通路和神经组织内免疫应答三者之间的联系，揭示天然免疫LIGHT信号促进神经节HSV-1增殖的细胞和分子机制。研究成果将为防治HSV-1感染性疾病提供重要理论依据。

淋巴毒素受体的配体LIGHT 是天然免疫抗感染的重要共刺激分子。本课题利用Rag-/-小鼠足垫皮下感染HSV-1 模型，分析神经节内LIGHT 信号通路、HSV-1 感染和炎症反应这三者之间的关系，我们的研究揭示了LT/LIGHT信号通路调节炎症反应促进神经组织中HSV-1病毒增殖的关键作用。为防止新生儿和免疫缺陷免疫抑制病人的致死性脑炎提供理论依据和新的思路，具有重要的科学意义应用前景。另外我们开展了关于淋巴毒素（LT）受体“LTβR信号通路调节HSV-1感染诱导的T细胞和抗体应答”的研究。进一步探索LTβR信号通路调节HSV-1感染诱导的免疫应答机制，不仅有助于加深我们对基础免疫学知识的了解，也有利于我们在疫苗开发中制定相应的特异性免疫治疗策略。在自然科学基金No. 81471579 的支持下，我们发表4篇较高质量的SCI科研论文。