神经肽Substance P调控HSV-1在三叉神经节内潜伏复发的分子机制研究

Herpes simplex keratitis (HSK) is a severe blinding eye disease caused by HSV-1. After primary infection, HSV-1 enters trigeminal ganglion (TG) for lasting latency, and leads to keratopathy through repeated recurrence, however, the mechanism of latency and recurrence is not clear until now. From the previous studies, we found that substance P (SP) was released from the TG after HSV-1 infection in cornea, and still maintained a relative higher level during latency. We also found that SP could activate Akt signaling in TG cells in vitro, promote HSV-1 latency and inhibit its reactivation; blocking SP induced HSV-1 reactivation; meanwhile, SP could promote TG cell survival. These suggested SP is a key factor to regulate HSV-1 latency and recurrence in TG. Based on the above findings, here we will further explore the key roles of SP inducing and maintaining HSV-1 latency, inhibiting its recurrence in TG, and illuminate the molecular mechanism of SP signaling pathway in regulation of HSV-1 latency and recurrence in TG, by using HSV-1 latent infection model in TG cells, HSK mouse model, and combined with the SP knock-out mouse. We will also evaluate the feasibility of using SP derived peptide for prophylaxis and treatment of recurrent HSK. The purpose of this study is to enrich the knowledge of neuropeptide involved in virus-host interaction theory, and provide the novel target and strategy for the clinical HSK therapy.

单疱病毒性角膜炎（HSK）是由HSV-1感染角膜引发的严重致盲性眼病。病毒原发感染后终生潜伏在三叉神经节内，反复复发引起角膜病变，目前对HSV-1潜伏复发的机制仍不清楚。我们前期的研究发现：Substance P（SP）在HSV-1感染角膜后的三叉神经节内大量释放，潜伏期仍维持较高水平；在体外，SP可活化三叉神经节细胞中的Akt信号，促进HSV-1的潜伏并抑制其复发，阻断SP信号则会诱导HSV-1复发，同时SP可促进神经细胞的存活。以上提示SP是调控HSV-1在三叉神经节内潜伏复发的关键。基于此，本项目拟通过HSV-1潜伏感染的神经细胞模型和HSK小鼠模型，并结合SP缺陷小鼠，深入研究SP诱导并维持HSV-1在三叉神经节内潜伏和抑制其复发的关键作用，阐明SP信号通路调控HSV-1潜伏复发的分子机制，并初步探讨利用SP衍生短肽防治HSK复发的可行性，为HSK的临床治疗提供新的靶标和干预策略。

本项目计划拟利用体外HSV-1潜伏感染的三叉神经节细胞模型和体内HSK小鼠模型，并结合SP缺陷小鼠，通过分子生物学和免疫学等实验手段，研究三叉神经节中自分泌的神经肽sp信号促进并维持HSV-1在三叉神经节内的潜伏、抑制其再活化的关键作用，为HSK的临床治疗提供新的药物靶标和干预策略。在项目执行过程中，我们围绕项目的主要目标进行了一系列的研究，一方面，确定了SP的自分泌信号通过Akt信号通路促进HSV-1在TG内潜伏、抑制其再活化；发现P物质通过调控STING/TBK1/IRF3信号通路表达，影响病毒复制以及抗病毒相关机制。另一方面，在本课题的资助下，开展了色素上皮细胞衍生因子PEDF、血管活性肠肽VIP对单纯疱疹病毒性角膜炎的作用探索以及选择性β2-肾上腺素受体拮抗剂ICI118551抑制绿脓杆菌角膜炎感染及其机制的研究。