JAK1-STAT6信号通路对肺泡巨噬细胞介导的抗弓形虫感染免疫调节机制的研究

Recently, there were much more case reports about pulmonary toxoplasmosis which was often overlooked or misdiagnosed in clinic and its pathogenesis is still unclear up to now. We are interested in the mechanism that why was the lung always be involved in disseminated toxoplasmosis? In fact, the theory and technology between macrophage polarization and pathogens were well developed lately. Morever, we speculate that the occurence of pulmonary toxoplasmosis is probably caused by the susceptibility of the parasite in alveolar macrophages and this perhaps is related to the tissue microenvironment and the “hijack” of alveolar macrophages which is result in the disorders of regulation of M1/M2 polarization by JAK1/STAT6 signaling pathway. Previous studies showed that Toxoplasma gondii can proliferate in rat and human alveolar macrophages, whereas are inhibited in there peritoneal macrophages; The mechanism of the difference is related to the expression and activity of iNOS/Arginase I. Therefore, we project to study the charicteristics of the parasitic infection in human alveolar macrophages by clinical samples, rat models, flow fluorescence technology, expression profile chip, RNAi and other methods and try to clarify the mechanism of JAK1/STAT6 signaling pathway which influence the M1/M2 macrophages polarization in the infection with different host immune status. Finally, we want to make the characteristic of the parasite infection in human alveolar macrophages clearly and to report possible molecular mechanism. Actually, to study the project is benefit for the clinicians on diagnosis, prevention and treatment for the disease.

肺弓形虫病的报道呈上升趋势。该病在临床上常常被忽视或误诊，其发病机制尚不清楚。令课题组感兴趣的是，为什么肺会成为播散性弓形虫病的受累组织？巨噬细胞极化与病原体感染的理论、技术目前已相对成熟，我们推测，肺弓形虫病的发生可能是由肺泡巨噬细胞感染弓形虫的特性决定的，和肺组织微环境及弓形虫“挟持”肺泡巨噬细胞JAK1/STAT6信号通路调控M1/M2极化有关。前期工作显示，弓形虫能够在大鼠和人肺泡巨噬细胞内增殖，在其腹腔巨噬细胞内则受抑制；大鼠肺泡和腹腔巨噬细胞感染弓形虫的差异机制和它们iNOS/Arginase I表达及活性有关。因此，课题组拟通过临床样本、大鼠模型、流式荧光技术、表达谱芯片、RNAi等手段，研究人肺泡巨噬细胞感染弓形虫的特性及JAK1/STAT6信号通路在感染过程中对M1/M2极化调节的影响，以期明确人肺泡巨噬细胞感染弓形虫的特性及可能的分子机制，为该病的诊疗提供基础研究支持。

本实验通过临床样本，大鼠模型，流式荧光技术，表达谱芯片，RNAi等手段，研究人肺泡巨噬细胞感染弓形虫的特异性及JAK1/STAT6信号通路在感染过程中对M1/M2极化调节的影响，以明确人肺泡巨噬细胞感染弓形虫的特异性及可能的分子机制，为诊断提供基础信息。通过对临床不同免疫状态的肺泡灌洗病人进行免疫状态和M1/M2 极化的测定，然后观察不同免疫状态下肺泡巨噬细胞感染弓形虫的特性，同时，对弓形虫感染与非感染情况下的肺泡巨噬细胞 mRNA 表达谱进行分析，以确定 M2 经典激活途径JAK1/STAT6 途径在弓形虫感染肺泡巨噬细胞过程中的作用。通过大鼠模型的制备，我们拟进一步研究在体内、 外环境下，肺泡巨噬细胞在免疫抑制、免疫激活等状态下应答弓形虫的特性，以期明确人肺泡巨噬细胞感染弓形虫的特性，并阐述 JAK1/STAT6 引起的 M2 极化在弓形虫感染肺泡巨噬细胞过程中的作用机制，从而为临床提供相关的分子病理研究基础。 结果发现弓形虫感染可以诱导大鼠巨噬细胞从静息状态极化为 M2 型；弓形虫RH株感染THP-1巨噬细胞后可以在胞内生长增殖，THP-1细胞感染后向Ｍ2型巨噬细胞方向极化；M1 型大鼠肺泡巨噬细胞可以明显抑制弓形虫的感染与增殖；弓形虫感染能诱导巨噬细胞表达M2型细胞炎性因子，并抑制M1型细胞因子的表达，可通过JAK1-STAT6信号通路调节人原代肺泡巨噬细胞向M2型巨噬细胞偏移。因此，本课题研究成果解释了临床不同疾病状态下新发或继发肺弓形虫病的免疫病理机制，为临床该病的诊断、防治提供基础研究支持。本课题共发表文章7篇（包括北大核心期刊5篇），培养研究生7名（包括3名毕业生和4名在读生）。

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