布鲁氏菌感染宿主细胞过程中NF-κB调控细胞凋亡的分子机制

Inhibition of cell apoptosis is an important strategy for bacterial intracellular Survival and reproduction. Cell transcription factor NF- kappa B is closely related to apoptosis, and is involved in the transcriptional regulation of many apoptosis related genes. Our previous studies showed that Brucella infection can inhibit host cell apoptosis, and Brucella virulent strain showed stronger inhibition than attenuated strain. Brucella infected host cells could activate NF- kappa B, but strong virulent strain had lower activation level of NF- kappa B than virulent strain. Now, It is not clear how NF- kappa B regulates the apoptosis signaling pathway during the infection of the host cells of Brucella.This project is on the basis of existing work, starting from the Brucella infection cells process, to explore the relationship between activation of NF- kappa B and cell apoptosis, comparative transcriptomics, proteomics, CHIP-seq screening and identification of Brucella virulent / attenuated strain infection on host cell in the process of NF- kappa B transcriptional regulation of the target gene of cell apoptosis, and study and analysis its biological function, apoptosis signaling pathways involved in the regulation of target genes to clarify the molecular mechanisms underlying the Brucella strains of virulent / attenuated activation of NF- kappa B and inhibit the cell apoptosis. It will provide a theoretical basis for elucidating the pathogenesis of Brucellosis.

抑制细胞凋亡是细菌胞内寄生的重要策略，细胞转录因子NF-κB与细胞凋亡关系密切，参与多种凋亡相关基因的转录调控。课题组前期研究表明：布鲁氏菌感染细胞过程中能抑制宿主细胞凋亡，布鲁氏菌强毒株比弱毒株表现出更强的抑制作用；布鲁氏菌感染宿主细胞能激活NF-κB，强毒株比弱毒株激活NF-κB水平低。目前布鲁氏菌感染宿主细胞的过程中NF-κB如何调控细胞凋亡信号通路的机制还不完全清楚。本项目拟在现有工作基础上，基于布鲁氏菌感染细胞过程，探讨布鲁氏菌激活NF-κB与细胞凋亡的关系，采用比较转录组学、蛋白组学、CHIP-seq等技术筛选并鉴定布鲁氏菌强/弱毒株感染宿主细胞过程中NF-κB转录调控的细胞凋亡相关靶基因，研究其生物学功能，阐明靶基因参与调控的细胞凋亡信号通路，揭示布鲁氏菌强/弱毒株激活NF-κB与抑制细胞凋亡作用的分子机制，为进一步阐明布鲁氏菌病致病机制提供理论依据。

布鲁氏菌病是由布鲁氏菌引起的一种自然疫源性、人兽共患传染性疾病，有研究表明，抑制细胞凋亡是布鲁氏菌维持胞内生存与复制的策略之一，布鲁氏菌可抑制宿主细胞凋亡，避免在细胞死亡后被机体的体液免疫和细胞免疫清除,从而保护其在宿主细胞内的长期寄生,并造成持续性感染。 本项目旨在明确布鲁氏菌感染宿主细胞过程中NF-KB信号通路与宿主细胞凋亡的关系，筛选并鉴定布鲁氏菌感染宿主细胞过程中NF-κB调控靶基因，揭示这些靶基因调控细胞凋亡相关的信号通路。项目通过构建布鲁氏菌侵染小鼠巨噬细胞感染模型，证实布鲁氏菌感染激活NF-KB信号通路；布鲁氏菌通过激活NF-KB信号通路抑制布鲁氏菌介导的宿主细胞凋亡；采用ChIP-Seq（染色质免疫共沉淀）技术筛选转录因子NF-κB调控靶基因，证实转录因子NF-κB通过靶基因gls参与布鲁氏菌感染引起细胞极化表型的转换及炎症反应；通过RNA测序、生物信息学分析与双荧光素酶酶报告系统，证实Gm28309是作为ceRNAs 通过miR-3068-5p 激活NF-κB途径，下调NF-κB-Ras2，促进NLRP3 炎症细胞的产生和 IL-1β、IL-18 的分泌。综上所述，项目研究结果为揭示布鲁氏菌致病机制提供理论基础，为寻找布鲁氏菌新的靶点提供依据，具有较高学术价值。项目实施过程中，培养博士生2名，硕士研究生4名，发表SCI收录论文5篇，发表中文论文3篇。参加国内外学术会议5次，获得自治区科研奖励1项，国际学术会议优秀论文1篇。

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