Laboratory for Molecular Infection Medicine Sweden, Umeå Centre for Microbial Research, Department of Molecular Biology, Umeå University, 90187, Umeå, Sweden.
INSERM U1138, Centre de Recherche des Cordeliers, 75006, Paris, France.
Cell Death Differ. 2019 Aug;26(8):1485-1500. doi: 10.1038/s41418-018-0224-2. Epub 2018 Oct 30.
Chlamydia trachomatis is an obligate intracellular bacterial agent responsible for ocular infections and sexually transmitted diseases. It has been postulated that Chlamydia inhibits apoptosis in host cells to maintain an intact replicative niche until sufficient infectious progeny can be generated. Here we report that, while cells infected with C. trachomatis are protected from apoptosis at early and mid-stages of infection, they remain susceptible to the induction of other cell death modalities. By monitoring the fate of infected cells by time-lapse video microscopy and by analyzing host plasma membrane integrity and the activity of caspases, we determined that C. trachomatis-infected cells exposed to pro-apoptotic stimuli predominately died by a mechanism resembling necrosis. This necrotic death of infected cells occurred with kinetics similar to the induction of apoptosis in uninfected cells, indicating that C. trachomatis fails to considerably prolong the lifespan of its host cell when exposed to pro-apoptotic insults. Inhibitors of bacterial protein synthesis partially blocked necrotic death of infected cells, suggesting that the switch from apoptosis to necrosis relies on an active contribution of the bacteria. Tumor necrosis factor alpha (TNF-α)-mediated induction of necrosis in cells infected with C. trachomatis was not dependent on canonical regulators of necroptosis, such as RIPK1, RIPK3, or MLKL, yet was blocked by inhibition or depletion of CASP8. These results suggest that alternative signaling pathways regulate necrotic death in the context of C. trachomatis infections. Finally, consistent with the inability of C. trachomatis to preserve host cell viability, necrosis resulting from pro-apoptotic conditions significantly impaired production of infectious progeny. Taken together, our findings suggest that Chlamydia's anti-apoptotic activities are not sufficient to protect the pathogen's replicative niche.
沙眼衣原体是一种专性细胞内细菌病原体，可引起眼部感染和性传播疾病。据推测，沙眼衣原体抑制宿主细胞凋亡，以维持完整的复制龛位，直到能够产生足够数量的传染性后代。在这里，我们报告称，尽管感染沙眼衣原体的细胞在感染的早期和中期受到抗凋亡保护，但它们仍然容易受到其他细胞死亡方式的诱导。通过延时视频显微镜监测感染细胞的命运，并分析宿主质膜完整性和半胱天冬酶的活性，我们确定感染沙眼衣原体的细胞在暴露于促凋亡刺激时主要通过类似于坏死的机制死亡。感染细胞的这种坏死性死亡与未感染细胞中凋亡的诱导动力学相似，表明沙眼衣原体在暴露于促凋亡刺激时并没有显著延长宿主细胞的寿命。细菌蛋白合成抑制剂部分阻断了感染细胞的坏死性死亡，表明从凋亡到坏死的转变依赖于细菌的积极贡献。TNF-α介导的感染沙眼衣原体的细胞坏死不依赖于坏死性凋亡的典型调节因子，如 RIPK1、RIPK3 或 MLKL，但被 CASP8 的抑制或耗尽所阻断。这些结果表明，替代信号通路在沙眼衣原体感染的情况下调节坏死性死亡。最后，与沙眼衣原体不能维持宿主细胞活力一致，促凋亡条件下的坏死严重损害了传染性后代的产生。综上所述，我们的研究结果表明，沙眼衣原体的抗凋亡活性不足以保护病原体的复制龛位。
