Site-specific contributions of glutamine-dependent regulator GlnR and GlnR-regulated genes to virulence of Streptococcus pneumoniae
Site-specific contributions of glutamine-dependent regulator GlnR and GlnR-regulated genes to virulence of Streptococcus pneumoniae
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DOI：
10.1128/iai.01004-07
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发表时间：
2008-03-01
影响因子：
3.1
通讯作者：
Hermans, Peter W. M.
中科院分区：
文献类型：
--
作者：
Hendriksen, Wouter T.;Kloosterman, Tomas G.;Hermans, Peter W. M.
肺炎链球菌的转录调节因子GlnR参与谷氨酰胺和谷氨酸代谢的调节，控制glnRA和glnPQ-zwf操纵子以及gdhA基因的表达。为了评估GlnR调节子对毒力的贡献，在体外粘附测定和鼠感染模型中测试了缺乏该调节子基因的D39野生型和突变株。所有的突变体，除了三角洲glnR突变体，衰减在坚持人咽上皮底特律562细胞，这表明这些基因的贡献，坚持在人类的殖民。在鼠定殖期间，与Δ glnA相反，仅Δ glnA突变体和glnP-glnA双突变体（Δ glnAP）被减弱，表明该效应是由缺乏GlnA表达引起的。在我们的肺炎模型中，只有Delta glnAP和Delta glnAP显示出肺和血液中细菌数量的显著减少，表明GlnAP是肺中存活所必需的，并且可能是传播到血液中所必需的。在静脉内感染的小鼠中，glnAP和glnA分别在血液中存活，而Δ glnAP突变体是无毒的。最后，Delta glnAP突变体的转录组分析表明，许多参与氨基酸代谢的基因被上调。这表明谷氨酰胺/谷氨酸摄取和合成对于细菌的完整适应性和毒力的重要性。总之，在发病过程中，GlnR调节子的几个基因需要在不同的位点，与glnA有助于定植和血液中的生存和glycoprotein重要的生存在肺中，并可能，有效的过渡从肺到血液。
The transcriptional regulator GlnR of Streptococcus pneumoniae is involved in the regulation of glutamine and glutamate metabolism, controlling the expression of the glnRA and glnPQ-zwf operons, as well as the gdhA gene. To assess the contribution of the GlnR regulon to virulence, D39 wild-type and mutant strains lacking genes of this regulon were tested in an in vitro adherence assay and murine infection models. All of the mutants, except the Delta glnR mutant, were attenuated in adherence to human pharyngeal epithelial Detroit 562 cells, suggesting a contribution of these genes to adherence during the colonization of humans. During murine colonization, only the Delta glnA mutant and the glnP-glnA double mutant (Delta glnAP) were attenuated, in contrast to Delta glnP, indicating that the effect is caused by the lack of GlnA expression. In our pneumonia model, only Delta glnP and Delta glnAP showed a significantly reduced number of bacteria in the lungs and blood, indicating that GlnP is required for survival in the lungs and possibly for dissemination to the blood. In intravenously infected mice, glnP and glnA were individually dispensable for survival in the blood whereas the Delta glnAP mutant was avirulent. Finally, transcriptome analysis of the Delta glnAP mutant showed that many genes involved in amino acid metabolism were upregulated. This signifies the importance of glutamine/glutamate uptake and synthesis for full bacterial fitness and virulence. In conclusion, several genes of the GlnR regulon are required at different sites during pathogenesis, with glnA contributing to colonization and survival in the blood and glnP important for survival in the lungs and, possibly, efficient transition from the lungs to the blood.