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首页> 外文期刊>Microbiology >Whole genome transcriptomics reveals global effects including up-regulation of Francisella pathogenicity island gene expression during active stringent response in the highly virulent Francisella tularensis subsp. tularensis SCHU S4
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Whole genome transcriptomics reveals global effects including up-regulation of Francisella pathogenicity island gene expression during active stringent response in the highly virulent Francisella tularensis subsp. tularensis SCHU S4

机译：全基因组转录组织揭示了全球效应，包括在高毒力<斜体>弗朗西氏菌Tularetensis 亚木中的主动严格响应期间对<斜体>毛颌骨>致病性岛屿基因表达的全局效应。 <斜体> tularensis Schu S4

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During conditions of nutrient limitation bacteria undergo a series of global gene expression changes to survive conditions of amino acid and fatty acid starvation. Rapid reallocation of cellular resources is brought about by gene expression changes coordinated by the signalling nucleotides' guanosine tetraphosphate or pentaphosphate, collectively termed (p)ppGpp and is known as the stringent response. The stringent response has been implicated in bacterial virulence, with elevated (p)ppGpp levels being associated with increased virulence gene expression. This has been observed in the highly pathogenic Francisella tularensis sub spp. tularensis SCHU S4, the causative agent of tularaemia. Here, we aimed to artificially induce the stringent response by culturing F. tularensis in the presence of the amino acid analogue l -serine hydroxamate. Serine hydroxamate competitively inhibits tRNA~(ser)aminoacylation, causing an accumulation of uncharged tRNA. The uncharged tRNA enters the A site on the translating bacterial ribosome and causes ribosome stalling, in turn stimulating the production of (p)ppGpp and activation of the stringent response. Using the essential virulence gene iglC , which is encoded on the Francisella pathogenicity island (FPI) as a marker of active stringent response, we optimized the culture conditions required for the investigation of virulence gene expression under conditions of nutrient limitation. We subsequently used whole genome RNA-seq to show how F. tularensis alters gene expression on a global scale during active stringent response. Key findings included up-regulation of genes involved in virulence, stress responses and metabolism, and down-regulation of genes involved in metabolite transport and cell division. F. tularensis is a highly virulent intracellular pathogen capable of causing debilitating or fatal disease at extremely low infectious doses. However, virulence mechanisms are still poorly understood. The stringent response is widely recognized as a diverse and complex bacterial stress response implicated in virulence. This work describes the global gene expression profile of F. tularensis SCHU S4 under active stringent response for the first time. Herein we provide evidence for an association of active stringent response with FPI virulence gene expression. Our results further the understanding of the molecular basis of virulence and regulation thereof in F. tularensis . These results also support research into genes involved in (p)ppGpp production and polyphosphate biosynthesis and their applicability as targets for novel antimicrobials.
机译：在营养限制细菌的条件下，经历一系列全球基因表达，以改变氨基酸和脂肪酸饥饿的活性。通过由信号传导核苷酸的鸟氨酸四磷酸盐或戊磷酸盐，共同称为（P）PPGPP的基因表达改变来快速重新分配细胞资源的变化，称为严格的响应。严格的反应涉及细菌毒力，升高（P）PPGPP水平与增加的毒力基因表达相关。这已在高致病性繁华的粗糙SUP SPP中观察到这一点。 Tularensis Schu S4，Tularemia的致病剂。在这里，我们旨在通过在氨基酸类似物L-羟肟酸盐存在下培养F. Tularensis来人为地诱导严格的响应。丝氨酸羟肟酸竞争性地抑制TRNA〜（SER）氨基酰化，导致不带电的TRNA积累。不带电的TRNA进入平移细菌核糖体上的部位，并导致核糖体停滞，反过来刺激（P）PPGPP的产生和活性响应的激活。使用基本毒力基因IgLC，其在毛茸的致病性岛（FPI）上编码为有源严格响应的标志物，我们优化了在营养限制条件下调查毒力基因表达所需的培养条件。我们随后使用全基因组RNA-SEQ来展示F. Tularensis在主动严格响应期间为全球规模改变基因表达。主要发现包括涉及毒力，应激反应和代谢的基因的上调，以及参与代谢物运输和细胞分裂的基因的下调。 F. Tularensis是一种高毒性的细胞内病原体，能够以极低的感染剂量导致衰弱或致命疾病。然而，毒力机制仍然很清楚。严格的响应被广泛识别为涉及毒力的多种和复杂的细菌应激反应。这项工作首次在主动严格响应下进行F. Tularensis Schu S4的全局基因表达谱。在此我们提供了与FPI毒力基因表达的主动严格响应协会的证据。我们的结果进一步了解F. Tularensis中的毒力和调节的分子基础。这些结果还支持研究（P）PPGPP生产和多磷酸盐生物合成的基因及其作为新型抗微生物的靶标的基因。

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