LT-II减毒突变体作为肠黏膜免疫佐剂的作用及其诱导黏膜免疫机制的研究

Enteric infection is one of the most important global public health problems. The intestinal mucosal immunity is the key measures to prevent this kind of disease. The mucosal immunologic adjuvant, which can enhance the mucosal immunogenicity of vaccine, is a key factor in the development of mucosal vaccines. The previous study showed that type II heat labile enterotoxin (LT-II) of Escherichia coli may possess the potential function as immunologic adjuvant. In addition, LT-II has a wide range of host and fewer side effects than LT-I, which was generally accepted as a safe immunologic adjuvant. Applicant firstly demonstrated that LT-IIc was the prevalent LT-II subtype in China, and the B subunit of LT-IIc has the equivalent immunologic adjuvant effect with LT-IB. However, the exact function and mechanism of LT-IIc as intestinal mucosal adjuvant is still unclear. In this program, in vivo and in vitro experiments will be performed for further exploring the relationship between the virulence determined amino acids and intestinal mucosal immune response, and exploring the function of the whole LT-IIc skeleton as intestinal mucosal adjuvant. Meanwhile, LT-IIc mediated intestinal mucosal immune pathway will be evaluated from three aspects including antigen presenting cell activation, immune effector cell maturation, and immunity signaling-pathways activation. This study has important significance for exploring the function and mechanism of LT-IIc as mucosal immune adjuvant, and providing important theoretical basis for the design and develop of mucosal vaccine for LT-IIc.

肠道传染病是全球性重要公共卫生问题之一，肠道黏膜免疫是科学防治此类疾病的关键措施。能够增强疫苗黏膜免疫原性的黏膜佐剂是黏膜疫苗开发中的关键。前期研究发现大肠杆菌II型不耐热肠毒素（LT-II）具有潜在的免疫佐剂功能，且比公认的安全佐剂LT-I宿主范围更广、副反应更小。申请人率先证明我国流行的LT-II是c亚型，且LT-IIcB具有与LT-IB相当的免疫佐剂效果，但LT-IIc确切的肠黏膜佐剂功能与机制尚不明确。本课题拟通过体内和体外实验进一步探讨LT-IIc骨架上决定毒力的关键氨基酸对其肠黏膜免疫应答的影响，及LT-IIc完整骨架作为肠黏膜免疫佐剂的作用；同时从LT-IIc参与的抗原提呈细胞活化，免疫效应细胞的成熟，免疫信号通路的激活三个方面阐明其介导肠黏膜免疫的途径。该研究对揭示LT-IIc黏膜免疫佐剂功能与机制具有重要意义，为基于LT-IIc的黏膜疫苗的设计和研发提供重要的理论依据。

肠道传染病是全球性重要公共卫生问题之一，肠道黏膜免疫是科学防治此类疾病的关键措施。能够增强疫苗黏膜免疫原性的黏膜佐剂是黏膜疫苗开发中的关键。前期研究发现大肠杆菌II型不耐热肠毒素（LT-II）具有潜在的免疫佐剂功能，且比公认的安全佐剂LT-I宿主范围更广、副反应更小。申请人率先证明我国流行的LT-II是c亚型，且LT-IIcB具有与LT-IB相当的免疫佐剂效果，但LT-IIc确切的肠黏膜佐剂功能与机制尚不明确。本课题拟通过体内和体外实验进一步探讨LT-IIc骨架上决定毒力的关键氨基酸对其肠黏膜免疫应答的影响，及LT-IIc完整骨架作为肠黏膜免疫佐剂的作用；同时从LT-IIc参与的抗原提呈细胞活化，免疫效应细胞的成熟，免疫信号通路的激活三个方面阐明其介导肠黏膜免疫的途径。该研究对揭示LT-IIc黏膜免疫佐剂功能与机制具有重要意义，为基于LT-IIc的黏膜疫苗的设计和研发提供重要的理论依据。