基于宿主细胞膜融合-MyD88通路探讨洁泽1号扶正解毒抗HSV-2作用的分子机制

Genital herpes caused by HSV-2 has been the higher risk of sexually transmitted diseases.Pregnant women with HSV-2 can endanger neonatal life and have high risk in the development of fetal nervous system defect. The infection of HSV-2 can serious influence on the quality of the population. However, there is no vaccine and pregnancy security medicine for HSV-2 infection. To explore the methods of effective prevention and treatment of HSV infection is the problem to be solved urgently. Based on the work foundation of JZ-No.1 in earlier stage, we established the cell model of transfection of HSV-2 in VK2/E6E7 successfully. We also found JZ-No.1 can inhibit the expression of the key molecular which mediate virus adhere, and intervene adhere and membrane fusion of virus and host cell, to provide the cytoprotection effect. Combined with the mechanisms of the host cell lesion induced by HSV-2 infection, this project intends to study the effect and mechanisms of JZ-No.1 and berberine, the king drug of JZ-No.1, which inhibit the fusion of HSV-2 virus and host cell membrane, and intervene the TLRs/MyD88/NF-kB signaling pathways to modulate the antiviral ability of host cell. This project not only intends to reveal the role and molecular mechanism of JZ-No.1 eliminating evil and anti-virus from two aspects of detoxification and strengthening body anti-virus ability, but provide a theoretical basis for clinical prevention and treatment of genital herpes, and further enrich the interpretation of scientific connotation and anti-virus infection mechanism of herbal medicines.

HSV-2病毒引起的生殖器疱疹是全世界高发的性传播疾病，妊娠合并HSV-2可危及新生儿生命和频发神经系统发育缺陷，严重影响出生人口质量，目前尚无有效疫苗和妊娠安全用药。探索有效防治HSV的方法一直是亟待解决的问题。课题基于前期中药复方洁泽1号的工作基础，成功建立HSV-2转染VK2/E6E7细胞模型并发现洁泽1号可抑制介导病毒黏附关键分子的表达,干预病毒与宿主细胞的粘附及膜融合，产生保护细胞效应。结合HSV-2感染致宿主细胞病变的机制，项目拟研究复方洁泽1号及其君药有效成分小檗碱抑制HSV-2病毒与宿主细胞膜融合的效应及机制，以及干预TLRs/MyD88/NF-kB信号转导通路而调节宿主细胞的抗病毒能力，从"解毒"、"扶正"两方面揭示中药复方洁泽1号"祛邪"抗HSV-2病毒的作用环节与分子机制，为临床预防及治疗生殖器疱疹提供新的理论依据。进一步丰富并诠释中药抗病毒感染机制的科学内涵。

生殖器疱疹（Genital Herpes ，GH）是一高发的性传播疾病，在女性生殖系统病毒性感染中居首位，属中医“带下”、“阴疮”范畴。妊娠早期感染HSV-2可通过胎盘传播，引起胎儿流产、新生儿畸形和或永久性神经损伤，严重影响出生人口质量。.课题基于前期中药复方洁泽1号的工作基础，结合HSV-2感染所致宿主细胞病变的机制，通过体外HSV-2感染宿主细胞VK2E6E7（人阴道永生化上皮细胞）为模型，研究洁泽1号及其君药的有效成分小檗碱对病毒HSV-2感染宿主细胞膜融合粘附、穿入、复制阶段的干预作用，发现洁泽1号体外抗HSV-2药效优于阳性对照组喷昔洛韦，不仅作用于病毒感染的早期阶段（膜融合粘附、穿入），同时在复制阶段也具有较好的抗病毒作用；以HSV-2小鼠为模型，通过整体动物实验验证体外实验结果，于洁泽1号凝胶阴道给药干预，发现中药复方洁泽1号具有较好的抗HSV-2作用,基于对TLRs-MyD88信号转导通路上、中、下游关键蛋白与效应分子（gD,TLRs,MyD88,TRIF/TICAM1蛋白,NF-kB, IL-1、IL-6、TNF-α、IFN-α、IFN-β等等）的影响，发现洁泽1号中药复方通过MyD88依赖和非MyD88依赖的信号途径诱导宿主天然免疫及提高机体获得性免疫，达到“扶正”以“解毒”的作用。.同时，整体动物实验和体外细胞学实验均表明中药复方洁泽1号抗HSV-2作用明显优于其君药的有效成分小檗碱，为揭示中药方剂君、臣、佐使配伍原则的科学内涵提供了实验依据。 .中药复方洁泽1号是在古方易黄汤的基础上，吸取现代中药研究成果加减化裁而成，具有“清热解毒，燥湿止带，收敛生肌”功效，课题研究结果显示，中药外用复方也是通过多环节，多靶点发挥抗HSV-2感染作用，丰富了中药复方治疗“带下病”的科学内涵，为进一步诠释中药抗病毒的作用制剂提供了新思路。

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