miR-150/Grail通路在免疫抑制宿主肺孢子菌肺炎中的作用机制

The incidence of PCP (Pneumocystis pneumonia) in HIV negative immunosuppressive population is increasing. In non-HIV-related PCP（NH-PCP）patients, glucocorticoid（GC） is an important risk factor. However, little is known about how GC alters the host defense against PCP. Our previous study focused on miRNA and mRNA expression profiling of the lung tissue of immunosuppressive PCP mice and wild type PCP mice. The results of bioinformatics prediction analysis and molecular biology experiments showed that compared with WT-PCP mice, miR-150 was significantly down-regulated in immunosuppressive PCP mice, and its target gene Grail was up-regulated. MiR-150 plays an important role in infection and immunity. Although the role of Grail in immunity system is partly reported, the molecular mechanism of Grail is still not clear. Thus, we aim to ① illuminate the cell distribution and immune regulatory mechanism of miR-150/Grail; ② clarify the effect of miR-150/Grail related pathway on the progression of disease in mice with PCP; ③ explore the reason why glucocorticoid induces NH-PCP. The study will provide basic data to the evaluation and treatment of NH-PCP.

HIV阴性的免疫抑制患者肺孢子菌肺炎（PCP）发病率逐渐升高，应用糖皮质激素是非HIV患者罹患PCP的重要因素，但激素导致患者易感肺孢子菌（PC）的机制并不清楚。我们对PC感染的免疫抑制小鼠及野生型小鼠肺组织行miRNA及mRNA表达谱分析，又经过实验确证：与野生型PCP小鼠相比，免疫抑制PCP小鼠肺组织中miR-150显著下调，miR-150预测的靶基因E3泛素蛋白连接酶Grail显著上调；miR-150表达下调是糖皮质激素与PC协同作用的结果。miR-150在感染免疫中具有重要作用，Grail与机体免疫虽有部分报道，但其分子机制仍不清楚。本项目将阐明miR-150/Grail的细胞分布及调控机制、明确miR-150/Grail相关通路对PCP小鼠疾病进展的影响、探索激素导致机体对PC易感的原因，为HIV阴性PCP患者的病情评估和治疗提供理论依据。

HIV阴性的免疫抑制患者肺孢子菌肺炎（PCP）发病率逐渐升高，应用糖皮质激素是非HIV患者罹患PCP的重要因素，但激素导致患者易感肺孢子菌（PC）的机制并不清楚。我们对PC感染的免疫抑制小鼠及野生型小鼠肺组织行miRNA表达谱分析，并且通过实验证实：糖皮质激素诱导的免疫抑制为miRNA表达改变的主要影响因素。免疫抑制小鼠肺泡巨噬细胞中miR-342-3p显著下调，miR-342-3p可能在免疫抑制小鼠肺泡巨噬细胞中发挥重要免疫调节功能。细胞功能实验显示，miR-342-3p可以影响巨噬细胞的凋亡与增殖活性，并且增强MHCⅡ分子的表达情况，以及提高巨噬细胞的吞噬能力。miRNA pull-down测序和蛋白质谱结合分析显示，miR-342-3p可以促进巨噬细胞产多种生巨噬细胞干扰素刺激因子(ISGs)，进而参与巨噬细胞在PC感染的免疫调控过程。以上研究提示miR-342-3p可能是免疫抑制患者感染肺孢子菌肺炎一个潜在的治疗靶点。