HPV11E7调控花生四烯酸代谢促进病毒免疫逃逸的机制研究

花生四烯酸代谢在细胞生命活动中具有重要作用，但其在HPV感染致肛门生殖器疣中的作用尚不明确。我们前期代谢组学和单细胞测序发现肛门生殖器疣中花生四烯酸代谢及其关键酶ALOX12B显著改变；干扰ALOX12B可抑制I型干扰素产生，而HPV11E7可显著抑制ALOX12B和m6A RNA甲基化酶METTL14表达；干扰METTL14可抑制ALOX12B表达。据此我们提出假说：HPV11E7下调METTL14介导的ALOX12B mRNA的m6A甲基化，抑制其表达，从而抑制花生四烯酸代谢和I型干扰素产生，削弱机体抗病毒免疫反应，促进免疫逃逸。本课题首先明确病毒感染下调花生四烯酸代谢的机制，尤其是m6A修饰在其中的作用；其次利用ALOX12B敲除小鼠研究其介导的花生四烯酸代谢对I型干扰素的调控。本研究从花生四烯酸代谢这个新视点探讨HPV感染免疫逃逸的发生机制，为复发性病毒感染性疾病的诊治提供新思路。

Arachidonic acid metabolisms play an important role in cell activities, but its role in anogenital warts induced by HPV infection remains unclear. Our previous metabonomics and single-cell sequencing showed that arachidonic acid metabolism and its key enzyme ALOX12B had changed significantly in anogenital warts. Interfering with ALOX12B can inhibit type I interferon production, HPV11 E7 can significantly inhibit ALOX12B and M6A RNA methylase METL14, while interfering with METL14 can inhibit the expression of ALOX12B. Therefore, we hypothesized that HPV11 E7 inhibited the expression of ALOX12B by down-regulating the M6A methylation of ALOX12B mRNA mediated by METTL14, thereby inhibiting arachidonic acid metabolism and the production of type I interferon, thus impairing host antiviral immune response and promoting immune escape. The study aims to clarify the mechanism of viral infection down-regulating arachidonic acid metabolism, especially M6A modification. Secondly, ALOX12B knockout mice were used to study the regulation of arachidonic acid metabolism on type I interferon. This study explored the immune escape mechanism in HPV infection from the new perspective of arachidonic acid metabolism. It provided a new idea for diagnosing and treating recurrent viral infectious diseases.