The Francisella tularensis migR, trmE, and cphA Genes Contribute to F. tularensis Pathogenicity Island Gene Regulation and Intracellular Growth by Modulation of the Stress Alarmone ppGpp
The Francisella tularensis migR, trmE, and cphA Genes Contribute to F. tularensis Pathogenicity Island Gene Regulation and Intracellular Growth by Modulation of the Stress Alarmone ppGpp
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DOI：
10.1128/iai.00073-13
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发表时间：
2013-08-01
影响因子：
3.1
通讯作者：
Jones, Bradley D.
中科院分区：
文献类型：
--
作者：
Faron, Matthew;Fletcher, Joshua R.;Jones, Bradley D.
土拉热弗朗西斯菌致病岛（FPI）编码许多毒力所需的蛋白质。这些基因的表达取决于FevR（PigR）调节剂及其与MglA/SspA和RNA聚合酶转录复合物的相互作用。鉴定FPI基因转录如何被激活的实验已经导致鉴定了migR、trmE和cphA基因内的突变，这些突变降低了FPI表达。最近的数据表明，由RelA和SpoT产生的小警报素ppGpp对于稳定弗朗西斯菌中的MglA/SspA和FevR（PigR）相互作用是重要的。通常已知ppGpp的产生被细菌中的细胞和营养应激激活，这表明细胞和营养应激充当FPI激活的重要信号。在这项工作中，我们证明了migR，trmE或cphA突变显着降低ppGpp积累。对于每种突变体，ppGpp水平的降低是相似的，并且与iglA报告基因表达的相应降低相关。此外，我们观察到这些突变体中的每一个在各种哺乳动物细胞内复制的能力存在差异，这表明migR、trmE和cphA基因可能是弗朗西斯菌中不同细胞应激反应途径的一部分。这些结果还表明，不同的哺乳动物细胞中存在不同的营养和细胞应激。这项工作提供了新的信息，以帮助了解弗朗西斯菌如何调节其毒力基因，以应对宿主细胞环境，它有助于我们不断增长的知识，这种非常成功的细菌病原体。
The Francisella tularensis pathogenicity island (FPI) encodes many proteins that are required for virulence. Expression of these genes depends upon the FevR (PigR) regulator and its interactions with the MglA/SspA and RNA polymerase transcriptional complex. Experiments to identify how transcription of the FPI genes is activated have led to identification of mutations within the migR, trmE, and cphA genes that decrease FPI expression. Recent data demonstrated that the small alarmone ppGpp, produced by RelA and SpoT, is important for stabilizing MglA/SspA and FevR (PigR) interactions in Francisella. Production of ppGpp is commonly known to be activated by cellular and nutritional stress in bacteria, which indicates that cellular and nutritional stresses act as important signals for FPI activation. In this work, we demonstrate that mutations in migR, trmE, or cphA significantly reduce ppGpp accumulation. The reduction in ppGpp levels was similar for each of the mutants and correlated with a corresponding reduction in iglA reporter expression. In addition, we observed that there were differences in the ability of each of these mutants to replicate within various mammalian cells, indicating that the migR, trmE, and cphA genes are likely parts of different cellular stress response pathways in Francisella. These results also indicate that different nutritional and cellular stresses exist in different mammalian cells. This work provides new information to help understand how Francisella regulates its virulence genes in response to host cell environments, and it contributes to our growing knowledge of this highly successful bacterial pathogen.