等位基因介导转录因子C/EBPβ和PU.1协同调控IL-1B表达的分子机制及其对结核菌感染转归的影响

IL-1β在结核菌感染过程中发挥免疫保护性和病理性双重作用，其表达调控机制异常复杂。我们前期发现：结核菌诱导巨噬细胞表达pro-IL-1B，并与C/EBPB、PU.1表达呈正相关；等位基因rs1143627影响IL-1β、IFN-γ分泌，并与结核病易感性、临床表型（肺内、肺外）密切相关；C/EBPβ、PU.1协同调控pro-IL-1B表达，rs1143627影响两者与IL-1B启动子结合能力。在此基础上，本项目拟探讨：1）C/EBPβ、PU.1协同调控IL-1B表达的作用形式，包括两者的直接作用、功能效应区以及与其它蛋白的交互作用；2）鉴定结核菌诱导C/EBPB、PU.1表达的关键细菌因子、受体及信号通路；3）借助“十二五”队列，评估IL-1B表达水平、多态性对预测结核菌感染转归（未进展、发病）的价值。项目将进一步阐明结核菌诱导IL-1B表达的转录调控机制，为结核病个体化免疫防治提供依据。

IL-1β plays a dual role of protective and pathogenic immunity during Mycobacterium tuberculosis infection, and its regulatory mechanism remains unclear. Our previous findings showed that M.tb infection triggered pro-IL-1B expression in macrophage, which positively correlated with transcription factor C/EBPB and PU.1 expression. As a functional SNP, the rs1143627 allele in the IL-1B gene promoter region affected IL-1β and IFN-γ secretion, meanwhile, the rs1143627 allele was associated with TB susceptibility and clinical phenotypes. Furthermore, the rs1143627 allele influenced the binding ability of C/EBPβ and PU.1 to the IL-1B promoter, which synergistically regulated pro-IL-1B expression. In this study, we will first investigate how to regulate pro-IL-1B expression by C/EBPβ and PU.1, involving the interaction between them, and interaction with other proteins. In addition, we will clarify the functional domains of C/EBPβ and PU.1 through designing series of truncated proteins. Secondly, we will identify the key bacterial factors, recognized receptors, and signal pathways to induce C/EBPB and PU.1 expression. Finally, since a LTBI cohort has been established during Twelve-fifth mega project, we will further explore the diagnosed value of IL-1B expression and polymorphisms to predict the clinical outcomes of M.tb infection. The results of this study will contribute to clarifying the transcription regulatory mechanism of IL-1B after M.tb infection, and provide a novel personally preventive strategy for TB.