PDF(Pubmed)
Abstract：
Malaria is a serious vector-borne disease characterized by periodic episodes of high fever and strong immune responses that are coordinated with the daily synchronized parasite replication cycle inside RBCs. As immune cells harbor an autonomous circadian clock that controls various aspects of the immune response, we sought to determine whether the intensity of the immune response to Plasmodium spp., the parasite causing malaria, depends on time of infection. To do this, we developed a culture model in which mouse bone marrow-derived macrophages are stimulated with RBCs infected with Plasmodium berghei ANKA (iRBCs). Lysed iRBCs, but not intact iRBCs or uninfected RBCs, triggered an inflammatory immune response in bone marrow-derived macrophages. By stimulating at four different circadian time points (16, 22, 28, or 34 h postsynchronization of the cells\' clock), 24-h rhythms in reactive oxygen species and cytokines/chemokines were found. Furthermore, the analysis of the macrophage proteome and phosphoproteome revealed global changes in response to iRBCs that varied according to circadian time. This included many proteins and signaling pathways known to be involved in the response to Plasmodium infection. In summary, our findings show that the circadian clock within macrophages determines the magnitude of the inflammatory response upon stimulation with ruptured iRBCs, along with changes of the cell proteome and phosphoproteome.
摘要：
疟疾是一种严重的媒介传播疾病，其特征是高热和强烈的免疫反应的周期性发作，与红细胞内每日同步的寄生虫复制周期相协调。由于免疫细胞拥有控制免疫反应各个方面的自主生物钟，我们试图确定对疟原虫的免疫反应强度。,导致疟疾的寄生虫，取决于感染时间。要做到这一点，我们开发了一种培养模型,其中感染伯氏疟原虫ANKA(iRBC)的红细胞刺激小鼠骨髓来源的巨噬细胞.裂解的iRBC，但不是完整的iRBC或未感染的RBC，在骨髓源性巨噬细胞中引发炎症免疫反应。通过在四个不同的昼夜节律时间点（细胞时钟同步后16、22、28或34小时）进行刺激，发现了活性氧和细胞因子/趋化因子的24小时节律。此外，对巨噬细胞蛋白质组和磷酸蛋白质组的分析显示，对iRBC的反应随昼夜节律时间而变化。这包括许多已知参与疟原虫感染反应的蛋白质和信号通路。总之,我们的研究结果表明，巨噬细胞内的生物钟决定了刺激破裂的iRBC时炎症反应的大小，随着细胞蛋白质组和磷酸蛋白质组的变化。
