疫苗免疫机理研究有两个基本科学问题，一是病原的哪些抗原是保护性抗原？二是调控保护性抗原被有效运送、递呈进而产生保护性免疫应答的机制为何？申请人近年从事转基因球虫及其免疫应答机制的研究表明，转基因球虫可激发宿主产生有效的针对外源抗原的免疫应答。因此本申请拟进一步利用转基因球虫模型来解析上述第二个问题。构建表达病毒蛋白、免疫受体配体、细胞因子等的转基因球虫及采用异源免疫策略来验证本申请提出的两个协同作用模式（假说）：一是宿主保护性免疫应答的产生系多因素协同作用的结果，即病原因素（免疫原性、空间位置、表达量、持续时间/方式）、宿主因素（免疫受体-配体和细胞因子）及感染方式（免疫策略）多个层面协同调控保护性免疫应答的产生；二是免疫受体-配体和免疫微环境通过协同作用促使树突状细胞将外源性抗原交叉递呈于MHCⅠ类途径。研究结果将为高效疫苗研制提供关键切入点和免疫学基础。

There are two basic questions to be addressed in the development of vaccines, one being which antigens are protective antigens from a pathogen, the other the mechanism controlling the presentation of a protective antigen and it’s elicitation of protective immunity in a host. Our recent studies demonstrate that transgenic Eimeria induced potent immune responses against expressed foreign antigens in chickens. Based on the current progress in immunology and our previous findings, we will address the second question mentioned above by the usage of transgenic Eimeria as a pathogen model. We will construct different transgenic Eimeria strains expressing protective proteins from avian influenza virus, ligands for immunoreceptors, cytokines and employ heterologous prime-boost vaccination regimes to test two hypotheses proposed in this proposal. One proposes that the induction of protective immunity could be regulated by combination of pathogen factors (immunogenicity, location, dose and duration of antigens), host factors (binding of its immunoreceptors by ligands and cytokine milieu) as well as infection mode (vaccination regimes); the other is that ligands binding to its pattern recognition receptor on the professional antigen-presenting cells together with cytokine milieu decide exogenous antigen to be cross-presented via the MHCⅠpathway. The most convincing and generalizable findings from this study will be the elucidation of the mechanism controlling the induction of protective immunity and the extracellular mechanism controlling cross-presentation, and will also provide a new perspective for studying immune correlates of protection for the state-of-the-art vaccine development in chickens and other livestock.