沙门氏菌长期感染小鼠模型中M2巨噬细胞分泌CXC趋化因子的能力及机制研究

Salmonella is estimated to cause 110 million illnesses around the world each year. China is in the area of medium burden with Salmonella. Approximately 5% infection cases turn to be longterm infection, however the molecular mechanism what prompt the acute infection continue to longterm infection remain to be defined. Salmonella was recently found to preferentially survive in macrophages with a M2 phenotype during the longterm infection. It is well known the ability of killing bacteria in M2 macrophage was reduced.According our earlier experiment in vitro, the CXC chemokines expressions decreased in the M2 macrophage. In the current project, mice infected with S. typhimurium will be used as the murine model of infection. FACs, Real-time PCR and Western Blot will be taken to analyze the expressions of CXC chemokines in the M2 macrophage. And with the above techniques, the contributions of IL10 and IL4 pathways to reduction of CXC chemokines in M2 macrophage will be determined. Overall, the variation and the mechanism of the capacity for secretion of CXC chemokines in M2 macrophage will be revealed during the longtern Salmonella infection in the murine model. This study is supposed to give a powerful supplement for the mechanism of persistent infection with Salmonella in the field of chemokine and macrophage, which may offer a fresh orientation for treatment with bacterial infection in the patient with different immune background.On the other hand, this project will provide evidence of experimental data with laboratory animal for precise medicine focused on the hypoimmunity.

全世界每年大约有1.1亿沙门氏菌感染病例，我国也处于中度暴发区。约5%沙门氏菌感染转为长期感染，但由急性转为长期感染的分子机制并不明确。研究发现长期感染时M2巨噬细胞为细菌增殖提供条件，我们前期研究已知细菌感染时M2巨噬细胞杀菌能力减弱，此外经初步体外实验发现M2巨噬细胞分泌CXC趋化因子减少。因此本项目拟以鼠伤寒沙门氏菌感染小鼠为感染模型，通过流式细胞分筛、荧光定量PCR、Western Blot等技术对M2巨噬细胞在细菌长期感染中分泌CXC趋化因子的能力进行分析，并对IL10、IL4等不同通路与M2巨噬细胞分泌CXC趋化因子减少的机制进行探索。旨在揭示沙门氏菌长期感染中M2巨噬细胞分泌CXC趋化因子能力变化，并从巨噬细胞和趋化因子方面进一步阐明沙门氏菌长期感染的分子机制，为不同免疫状况患者细菌感染治疗提供思路，为针对机体免疫状况的精准医疗提供实验动物学数据支撑。

全世界每年大约有1.1亿沙门氏菌感染病例，我国也处于中度暴发区。约5%沙门氏菌感染转为长期感染，但由急性转为长期感染的分子机制并不明确。长期感染时M2巨噬细胞为细菌增殖提供条件，本项目以鼠伤寒沙门氏菌感染小鼠为感染模型，通过流式细胞分筛、荧光定量PCR、Western Blot等技术以及体内外实验对M2巨噬细胞在细菌长期感染中分泌CXC趋化因子的能力进行分析，发现沙门氏菌感染改变巨噬细胞趋化因子及其受体的转录与表达；M1型和M2型激活巨噬细胞趋化因子及其受体的转录和表达模式改变并有明显差异；进而发现不同途径激活的巨噬细胞对沙门氏菌感染的应答差异显著；通过对其分子机制进行分析，从IL10、IL4等不同通路着手，研究了M2巨噬细胞感染沙门氏菌时分泌CXC趋化因子减少的机制。揭示了沙门氏菌长期感染中M2巨噬细胞分泌CXC趋化因子能力变化，并从巨噬细胞和趋化因子方面进一步阐明沙门氏菌长期感染的分子机制，证实IL-10/STAT3信号通路在其中的作用，并证实IL-10/STAT3不是唯一影响因素；发现IL-4激活M2巨噬细胞中的MEK/ERK与CXC趋化因子分泌有直接关系。从而证实沙门氏菌感染中M2巨噬细胞的CXC趋化因子分泌能力受损，从而为沙门氏菌长期感染提供条件。从分子机制方面分析沙门氏菌感染小鼠模型中M2巨噬细胞的CXC趋化因子分泌能力受损的原因，特别是根据NFκB信号通路与C/EBPβ信号通路两个方向分别探明IL-10/STAT3和IL-4激活的MEK/ERK信号通路与CXC趋化因子分泌能力不足的关系，阐明M2巨噬细胞在沙门氏菌长期感染机制中的具体作用，为了解沙门氏菌与宿主的相互作用提供有力的补充，为沙门氏菌的防治提供思路。

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