Laboratory of Microbiology, Department of Food and Nutritional Sciences, Graduate School of Integrated Pharmaceutical and Nutritional Sciences, University of Shizuoka, Shizuoka, Japan.
Laboratory of Veterinary Public Health, School of Veterinary Medicine, Faculty of Veterinary Science, Nippon Veterinary and Life Science University, Tokyo, Japan.
Microbiol Immunol. 2020 Apr;64(4):270-279. doi: 10.1111/1348-0421.12770. Epub 2020 Jan 21.
Anaplasma phagocytophilum, an obligate intracellular bacterium that propagates within host granulocytes, is considered to modify the host intracellular environment for pathogenesis. However, the mechanism(s) underlying such host modifications remain unclear. Here, we aimed to investigate the relation between A. phagocytophilum and endoplasmic reticulum (ER) stress in THP-1 cells. A. phagocytophilum activated the three ER stress sensors: inositol-requiring enzyme-1 (IRE1), protein kinase RNA-like endoplasmic reticulum kinase (PERK), and activating transcription factor-6 (ATF6). IRE1 activation occurred immediately after host cell invasion by A. phagocytophilum; however, the activated IRE1-induced splicing of X-box-binding protein 1 was not promoted during A. phagocytophilum infection. This suppression was sustained even after the doxycycline-mediated elimination of intracellular A. phagocytophilum. IRE1 knockdown accelerated A. phagocytophilum-induced apoptosis and decreased intracellular A. phagocytophilum. These data suggest that A. phagocytophilum utilizes IRE1 activation to promote its own intracellular proliferation. Moreover, PERK and ATF6 partially mediated A. phagocytophilum-induced apoptosis by promoting the expression of CCAAT/enhancer-binding protein homologous protein, which induces the transcription of several proapoptotic genes. Thus, A. phagocytophilum possibly manipulates the host ER stress signals to facilitate intracellular proliferation and infection of surrounding cells before/after host cell apoptosis.
细胞浆内专性寄生菌嗜吞噬细胞无形体通过在宿主粒细胞内繁殖来改变宿主细胞内环境，从而促进疾病发生。然而，宿主发生改变的机制尚不清楚。本研究旨在探讨嗜吞噬细胞无形体与内质网（ER）应激在 THP-1 细胞中的关系。嗜吞噬细胞无形体激活了三种 ER 应激传感器：肌醇需求酶 1（IRE1）、蛋白激酶 RNA 样内质网激酶（PERK）和激活转录因子 6（ATF6）。IRE1 在嗜吞噬细胞无形体感染宿主细胞后立即被激活；然而，IRE1 诱导的 X 盒结合蛋白 1 的剪接在嗜吞噬细胞无形体感染过程中并未得到促进。即使在用强力霉素消除细胞内嗜吞噬细胞无形体后，这种抑制仍持续存在。IRE1 的敲低加速了嗜吞噬细胞无形体诱导的细胞凋亡并减少了细胞内的嗜吞噬细胞无形体。这些数据表明，嗜吞噬细胞无形体利用 IRE1 的激活来促进自身的细胞内增殖。此外，PERK 和 ATF6 通过促进 CCAAT/增强子结合蛋白同源蛋白的表达部分介导了嗜吞噬细胞无形体诱导的细胞凋亡，从而诱导了几个促凋亡基因的转录。因此，嗜吞噬细胞无形体可能在宿主细胞凋亡前后操纵宿主 ER 应激信号，以促进细胞内增殖和感染周围细胞。
