IL-33促进狂犬病病毒免疫原性的机制研究

狂犬病是由狂犬病病毒（RABV）引起的人兽共患传染病，其发病后死亡率高达100%。97%以上的人狂犬病病例为犬传播，而犬免疫覆盖率升至70%以上可有效控制人间狂犬病。然而，我国犬只数量巨大；当前使用的狂犬病灭活疫苗早期免疫效果不理想，并需多次免疫，难以在我国推广应用，使得犬免疫覆盖率仅有3%-5%；有关白介素-33（IL-33）在狂犬病方面的研究尚未报道。我们前期研究发现单剂量免疫表达IL-33的重组RABV能较快产生高水平中和抗体，并维持长达8周，但以上作用机制尚不清楚。因此，本项目拟运用反向遗传系统、小鼠免疫模型、流式细胞术和免疫组化等技术明确IL-33是否通过成熟树突状细胞激活先天性免疫来影响RABV诱导的早期免疫抗体的产生？是否通过调控依赖T细胞的生发中心反应来影响免疫7天后的体液免疫？从而，阐明IL-33促进RABV免疫原性的机制，为犬新型疫苗的研发提供依据，并缓和“人狗矛盾”。

Rabies, caused by rabies virus (RABV), is an infectious zoonosis with destroyed central nervous system. Once the clinical symptoms of rabies appear, the mortality is almost up to 100%. More than 97% human rabies cases are related to dogs bite. The mass vaccination of domestic dogs (>70%) has nearly eliminated cases of human rabies. However, the large amount of dogs leads to the severe contradiction between human and stray dogs. The early immunization effect of rabies animal vaccines we used is not ideal. And inactivated vaccines that need multiple immunizations are difficult to be used widely in China. Currently, studies on IL-33 related to rabies are not yet reported. Our previous studies shown that the RABV expressing IL-33 could induce early virus-neutralizing antibody and keep high levels at least three weeks safely. However, the related mechanism is not clear. Therefore, in this study, we will use the reverse genetic technology, mouse model of RABV immune, flow cytometry and immunofluorescence to investigate the role of IL-33 in the immune response induced by RABV. Whether IL-33 affects the production of RABV-induced early immune antibodies through activation of innate immunity by dendritic cells maturation? Whether IL-33 affects humoral immunity 7 days after immunization by regulating CD4 T Cell-dependent germinal center response? This study will provide an enhanced understanding for mechanism of immunogenicity of RABV, lay the fundation for the development of novel dog RABV vaccines, and ease the contradiction between human and dogs.