IL-17A在肺炎链球菌急性中耳炎黏膜免疫保护中的作用

Streptococcus pneumoniae is the most common cause of acute otitis media. Vaccine may be an effective strategy in the prevention of pneumococcal diseases. Antibody has been long considered to play a key role on prevention of pneumococcal diseases. However, the pneumococcal vaccines which mainly induce antibody in the market play limited protective roles on acute otitis media. In recent years, studies have confirmed IL-17A mediated acquired immunity to pneumococcal colonization. However, the role of IL-17A in mucosal immunity against pneumococcal otitis media remained unknown.BALB/c mice were immunized intranasally with pneumococcal surface antigen A (PsaA) using chitosan as an mucosal delivery system and the protecive roles against pneumococcal otitis media have been confirmed in our previous studies. We also found that the IL-17A was higher in the bronchoalveolar lavage fluids in the vaccined groups than in the non-vaccined groups in our preliminary studies. Our future studies will focus on the evaluation of roles of IL-17A in mucosal immunity against pneumococcal otitis media.The research contents as follows:1) The establishment of animal models of acute pneumococcal otitis media and the roles in innate immunity of pneumococcal otitis media; 2) Mice were immunized intranasally with PsaA vaccines and the roles of IL-17A in mucosal adaptive immunity against pneumococcal otitis media were explored. In summary, in the study, we expected that IL-17A may play a key role in mucosal immunity against pneumococcal otitis media, which will provide theoretical basis for the design of new generation pneumococcal vaccines and the mucosal immune strategy.

肺炎球菌是急性中耳炎最常见病原菌，疫苗是减少中耳炎的有效手段，抗体一直被认为是肺炎球菌疾病的主要防御机制，而目前市场上现有的主要产生抗体的疫苗对急性中耳炎的保护力很有限。IL-17A是调节固有免疫和获得性免疫的重要因子，已有研究证实IL-17A在预防肺炎球菌鼻咽部定植中的作用，但在急性中耳炎黏膜免疫中的作用无相关研究。前期我们采用新型肺炎球菌蛋白疫苗经鼻腔途径免疫小鼠，已证实对急性中耳炎的保护作用，并初步发现黏膜中IL-17A的分泌增多，本课题将探讨IL-17A在肺炎链球菌急性中耳炎黏膜免疫保护中的作用，研究内容为1）建立肺炎球菌急性中耳炎动物模型，研究IL-17A在急性中耳炎固有免疫中的作用；2）新型肺炎球菌蛋白疫苗黏膜途径免疫，研究IL-17A在适应性黏膜免疫保护的作用。通过上述研究，力图阐明IL-17A是肺炎球菌急性中耳炎黏膜免疫的主要防御机制，为新一代疫苗的设计及免疫策略提供依据。

我们经鼓膜和听泡途径建立了小鼠肺炎链球菌急性中耳炎模型；制备新型肺炎球菌PsaA蛋白疫苗，以壳聚糖（chitosan）作为黏膜输送系统和霍乱毒素B(CTB)作为佐剂，经鼻腔途径免疫小鼠，均在体内诱导了较强的免疫反应并且对急性中耳炎均产生了保护作用，发现黏膜免疫后脾上清分泌了较高水平的IL-17A，中耳攻毒后中耳黏膜灌洗液中也检测到较高水平IL-17A，相关细胞因子CXCL2、CXCL5水平增高，中耳黏膜IL-6、防御素β2、CXCL2 mRNA表达量明显增高，均提示IL-17A在中耳适应性黏膜免疫保护中起重要作用；在固有免疫中，中和体内的IL-17A，感染肺炎链球菌后，中耳有更严重的炎症反应，且中耳IL-17A、CXCL2、CXCL5分泌减少，提示IL-17A在肺炎链球菌急性中耳炎的固有黏膜免疫防御中起重要作用。本项研究制备了新型肺炎球菌蛋白疫苗，证实了IL-17A在肺炎链球菌急性中耳炎黏膜免疫保护中起重要作用，为新一代疫苗的设计及免疫策略的选择提供了实验依据。