HPV11E7蛋白抑制Imiquimod介导的角质形成细胞TLR7信号和I型干扰素的产生

尖锐湿疣（CA)是我国发病率最高的性传播疾病之一，主要由人乳头瘤病毒6型和11型引起。5％咪喹莫特乳膏（imiquimod，TLR7激动剂）能在局部诱导免疫细胞产生I型干扰素，起到间接抗病毒作用，常应用于治疗CA，但是，其复发率仍高达26％。因此研究低危型HPV病毒的免疫逃逸机制具有重要的意义。我们前期实验结果显示HPV11E7能够抑制imiquimod诱导KC细胞TLR7的表达从而抑制由imiquimod诱导产生的I型干扰素。基因芯片结果显示，HPV11E7能够上调组蛋白去甲基化酶KDM2B的表达。本项目将利用免疫共沉淀技术以及CHIP等实验进一步研究HPV11E7对imiquimod诱导KC细胞产生I型干扰素信号通路的分子机制以及对TLR7表达变化的表观调控机制。本研究的完成有望揭示HPV11型病毒的免疫逃逸的新机制，为抵御HPV11型病毒感染和CA的治疗及复发提供新的思路。

Condyloma acuminatum (CA) is a common sexually transmitted disease mainly caused by human papillomavirus (HPV) 6 and 11 infections. TLR7 agonists imiquimod is often used to treat CA by promoting the production of type I interferon in immune cells. However, TLR7 gene does not express in keratinocytes and express lowly in HaCaT cells and the function and mechanisms of imiquimod is unclear in keratinocytes. Here, we found the expression of TLR7 could induced by imiquimod, which was critical for the production of type I interferon induced by imiquimod in keratinocytes. Also, we found HPV11E7 dramatically inhibited the expression the TLR7 and the production of type I interferon. Microarray analysis showed that HPV11E7 significantly upregulated the lysine (K)-specific demethylase 2B (KDM2B) mRNA which preferentially demethylates trimethylated H3 Lys-4 and dimethylated H3 Lys-36 residue. We will further explore the mechanisms how HPV11E7 inhibit the type I interferon signal pathway and the epigenetic regulatory mechanisms how HPV11E7 inhibit the expression of TLR7 in keratinocyte. Our results will show HPV11E7 decreased the production of type I interferon by up egulating the KDM2B mRNA which could regulate the expression of TLR7. These findings provide insights into the immunological escape mechanism of HPV and drug resistance to imiquimod.