Huang Yanru, Li Sijia, He Siqin, Li Yumeng, He Qingzhi, Wu Yimou
Institute of Pathogenic Biology, Hengyang Medical School, University of South China, Hunan Province Cooperative Innovation Center for Molecular Target New Drug Study, University of South China, Hunan Provincial Key Laboratory for Special Pathogens Prevention and Control, University of South China, Hengyang 421001, Hunan, China.
Institute of Pathogenic Biology, Hengyang Medical School, University of South China, Hunan Province Cooperative Innovation Center for Molecular Target New Drug Study, University of South China, Hunan Provincial Key Laboratory for Special Pathogens Prevention and Control, University of South China, Hengyang 421001, Hunan, China; Department of Clinical Laboratory, The First Affiliated Hospital of University of South China, Hengyang 421000, Hunan, China.
Int J Biochem Cell Biol. 2023 Apr;157:106376. doi: 10.1016/j.biocel.2023.106376. Epub 2023 Jan 28.
Chlamydia psittaci is a multi-host zoonotic pathogen, which mainly infects poultry and inflicts an appreciable economic burden on the livestock farming industry. C. psittaci inclusion membrane proteins are uniquely positioned at the host-pathogen interface and are important virulence proteins. We have previously confirmed that Incs regulate host cell survival to help Chlamydia sp. evade host-cell-mediated defense mechanisms. However, the role of the Inc, CPSIT_0842, in the regulation of cell death following the establishment of persistent C. psittaci infection remains unknown. This study explored the effect of CPSIT_0842 on the crosstalk between the autophagic and apoptotic pathways in macrophages. Results showed that CPSIT_0842 initiated autophagy and blocked autophagic flux in human macrophages, as indicated by autophagy-related protein LC3-II, Beclin-1, and p62 upregulation, autophagosome accumulation, and lysosomal protein LAMP1 diminution. We also showed that the disruption of autophagic flux had a regulatory effect on CPSIT_0842-induced apoptosis. Moreover, the suppression of autophagy initiation by 3-methyladenine attenuated CPSIT_0842-induced apoptosis. By contrast, the induction of autophagic flux by rapamycin did not significantly affect CPSIT_0842-induced apoptosis. Taken together, these findings demonstrate that CPSIT_0842 induced macrophage apoptosis by initiating incomplete autophagy through the MAPK/ERK/mTOR signaling pathway, which may be instrumental to the ability of C. psittaci to evade the host innate immune response and establish persistent infection. The improved understanding of the autophagic and cell death pathways triggered upon bacterial inclusion will likely help in the development of novel treatment strategies for chlamydia infection.
鹦鹉热衣原体是一种可感染多种宿主的人畜共患病原体，主要感染家禽，给畜牧业造成了相当大的经济负担。鹦鹉热衣原体包涵体膜蛋白独特地位于宿主 - 病原体界面，是重要的毒力蛋白。我们之前已经证实，包涵体膜蛋白可调节宿主细胞存活，以帮助衣原体属逃避宿主细胞介导的防御机制。然而，包涵体膜蛋白CPSIT_0842在鹦鹉热衣原体持续性感染建立后对细胞死亡调节中的作用仍不清楚。本研究探讨了CPSIT_0842对巨噬细胞自噬和凋亡途径之间相互作用的影响。结果显示，自噬相关蛋白LC3-II、Beclin-1和p62上调、自噬体积累以及溶酶体蛋白LAMP1减少表明，CPSIT_0842在人巨噬细胞中引发了自噬并阻断了自噬流。我们还表明，自噬流的破坏对CPSIT_0842诱导的凋亡具有调节作用。此外，3-甲基腺嘌呤抑制自噬起始可减弱CPSIT_0842诱导的凋亡。相比之下，雷帕霉素诱导自噬流并未显著影响CPSIT_0842诱导的凋亡。综上所述，这些发现表明，CPSIT_0842通过MAPK/ERK/mTOR信号通路引发不完全自噬来诱导巨噬细胞凋亡，这可能有助于鹦鹉热衣原体逃避宿主固有免疫反应并建立持续性感染。对细菌包涵体引发的自噬和细胞死亡途径的深入了解可能有助于开发针对衣原体感染的新型治疗策略。
