Intracellular proliferation of Anaplasma phagocytophilum is promoted via modulation of endoplasmic reticulum stress signaling in host cells
Intracellular proliferation of Anaplasma phagocytophilum is promoted via modulation of endoplasmic reticulum stress signaling in host cells
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DOI：
10.1111/1348-0421.12770
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发表时间：
2020-01
影响因子：
2.6
通讯作者：
Y. Yoshikawa;K. Sugimoto;Y. Ochiai;N. Ohashi
中科院分区：
文献类型：
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作者：
Y. Yoshikawa;K. Sugimoto;Y. Ochiai;N. Ohashi
嗜吞噬细胞无形体是一种在宿主粒细胞内繁殖的专性细胞内细菌，被认为改变宿主细胞内环境以致病。然而，这种宿主修饰的机制仍不清楚。本文旨在探讨A. THP-1细胞中的嗜吞噬细胞和内质网（ER）应激。A.嗜吞噬细胞菌激活了三种ER应激传感器：肌醇需要酶-1（IRE 1）、蛋白激酶RNA样内质网激酶（PERK）和激活转录因子-6（ATF 6）。IRE 1在A.然而，活化的IRE 1诱导的X-box-binding protein 1剪接在A.嗜吞噬细胞菌感染即使在多西环素介导的细胞内A消除后，这种抑制也持续存在。嗜吞噬细胞菌IRE 1敲除加速A.嗜吞噬细胞菌诱导的细胞凋亡和减少细胞内A.嗜吞噬细胞菌这些数据表明A.嗜吞噬细胞菌利用IRE 1活化来促进其自身的细胞内增殖。此外，PERK和ATF 6部分介导A.嗜吞噬细胞菌通过促进CCAAT/增强子结合蛋白同源蛋白的表达诱导细胞凋亡，该同源蛋白诱导几种促凋亡基因的转录。因此，A.嗜吞噬细胞菌可能操纵宿主内质网应激信号，以促进宿主细胞凋亡前后的细胞内增殖和周围细胞的感染。
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.