METTL3介导的DC m6A修饰在HBsAg阳性母亲婴儿乙肝疫苗无弱应答中的作用

HBsAg阳性母亲婴儿乙肝疫苗无弱应答率高，是HBV感染和乙型肝炎流行的重要原因，但机制不明。课题组在前期研究基础上，拟从疫苗应答最关键的抗原提呈细胞——树突状细胞（DC）入手，结合人群研究、动物实验和体外实验，探讨甲基转移酶样蛋白3（METTL3）介导的DC和HBV N6-甲基腺嘌呤（m6A）修饰对婴儿乙肝疫苗无弱应答的作用及机制。采用巢式病例对照研究探讨母儿DC m6A修饰相关通路分子事件的变化特点及其关系和母亲HBV m6A修饰对婴儿乙肝疫苗无弱应答的影响；动物实验比较METTL3基因敲除与野生型小鼠乙肝疫苗免疫应答的不同；体外实验以METTL3过表达/沉默的DC与m6A修饰的HBV刺激后的PBMC共培养，观察重组HBsAg干预后的免疫应答特点；探讨 METTL3介导的DC m6A修饰对婴儿乙肝疫苗应答的作用，初步阐明其作用机制及逆转无弱应答的可能性，为降低其发生率提供新思路。

The high rate of non-/hypo-response to hepatitis B vaccine in infants born to HBsAg-positive mothers was a major challenge in preventing hepatitis B infection. Based on our previous research, we propose to start with dentritic cell (DC), the most important antigen presenting cell in vaccine response, to conduct a population study, an animal study, and an in vitro study to explore the effects and mechanisms of mettl3-mediated N6-methyladenosine (m6A) modification of DC and HBV on infants’ non-/hypo-response to hepatitis B vaccine under HBV m6A modification. To be specific, we propose to examine the maternal and infants’ DC and HBV m6A modification and the related signal pathway molecules, and to explore their influence on infants’ non-/hypo-response to hepatitis B vaccine with nested case-control study; to compare the different immune response to hepatitis B vaccine between mettl3 knockout mice and wild type mice; and to employ an in vitro study through co-cultivating PBMC with m6A modified HBV, mettl3-suppressed or mettl3-overexpressed DC and then stimulated with recombinant HBsAg, in order to investigate the role of mettl3-mediated DC m6A modification on infants’ non-/hypo-response to hepatitis B vaccine under HBV m6A modification. This study has the potential to illuminate novel mechanism underlying non-/hypo-response to hepatitis B vaccine and subsequently improve infants’ immune response to hepatitis B vaccine.