NF-κB-dependent inhibition of apoptosis is essential for host cell survival during Rickettsia rickettsii infection
NF-κB-dependent inhibition of apoptosis is essential for host cell survival during Rickettsia rickettsii infection
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DOI：
10.1073/pnas.95.8.4646
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发表时间：
1998-04-14
影响因子：
11.1
通讯作者：
Sporn, LA
中科院分区：
文献类型：
--
作者：
Clifton, DR;Goss, RA;Sporn, LA
利用立克次体（Rickettsia rickettsii），一种专性细胞内革兰氏阴性菌，是落基山斑疹热的病原体，探讨了细菌可能已经进化出克服宿主细胞凋亡的策略的可能性。血管内皮细胞，在体内感染期间的主要靶细胞，在自然感染期间没有表现出凋亡的证据，并且在由于坏死性损伤而最终死亡之前维持足够的时间以允许复制和细胞间扩散。本实验室先前的工作表明，R.立克次氏体感染激活转录因子NF-κ B并改变其控制下的几个基因的表达。然而，当R.立克次氏体诱导的NF-κ B B活化被抑制，感染而非未感染的内皮细胞迅速发生凋亡。此外，用使NF-κ B失活的超阻遏物突变体抑制性亚基I κ B稳定转染的人胚胎成纤维细胞在感染时也经历了凋亡，而感染的野生型人胚胎成纤维细胞存活。R.因此，立克次氏体似乎通过依赖于NF-κ B活化的机制抑制宿主细胞凋亡。细胞核凋亡的变化与细胞内生物体的存在相关，因此这种以前未被识别的促凋亡信号被伴随的NF-κ B激活所掩盖。可能需要细胞内感染我们的研究表明，细菌生物体可以发挥抗凋亡作用，从而调节宿主细胞的凋亡反应，使其自身的优势，潜在地允许宿主细胞保持作为感染部位。
The possibility that bacteria may have evolved strategies to overcome host cell apoptosis was explored by using Rickettsia rickettsii, an obligate intracellular Gram-negative bacteria that is the etiologic agent of Rocky Mountain spotted fever. The vascular endothelial cell, the primary target cell during in vivo infection, exhibits no evidence of apoptosis during natural infection and is maintained for a sufficient time to allow replication and cell-to-cell spread prior to eventual death due to necrotic damage. Prior work in our laboratory demonstrated that R. rickettsii infection activates the transcription factor NF-kappa B and alters expression of several genes under its control. However, when R. rickettsii-induced activation of NF-kappa B was inhibited, apoptosis of infected but not uninfected endothelial cells rapidly ensued. In addition, human embryonic fibroblasts stably transfected with a superrepressor mutant inhibitory subunit I kappa B that rendered NF-kappa B inactivatable also underwent apoptosis when infected, whereas infected wild-type human embryonic fibroblasts survived. R. rickettsii, therefore, appeared to inhibit host cell apoptosis via a mechanism dependent on NF-kappa B activation. Apoptotic nuclear changes correlated with presence of intracellular organisms and thus this previously unrecognized proapoptotic signal, masked by concomitant NF-kappa B activation. likely required intracellular infection. Our studies demonstrate that a bacterial organism can exert an antiapoptotic effect, thus modulating the host cell's apoptotic response to its own advantage by potentially allowing the host cell to remain as a site of infection.