Two coregulated efflux transporters modulate intracellular heme and protoporphyrin IX availability in Streptococcus agalactiae.
Two coregulated efflux transporters modulate intracellular heme and protoporphyrin IX availability in Streptococcus agalactiae.
复制标题
DOI：
10.1371/journal.ppat.1000860
复制
发表时间：
2010-04-22
期刊：
影响因子：
6.7
通讯作者：
Gruss A
中科院分区：
文献类型：
--
作者：
Fernandez A;Lechardeur D;Derré-Bobillot A;Couvé E;Gaudu P;Gruss A
无乳链球菌是一种主要的新生儿病原体，其感染途径包括败血症。这种病原体不合成血红素，但从血液中清除血红素以激活呼吸代谢，从而增加细菌细胞密度，这是完全毒力所必需的。调节无乳草血红素库的因素尚不清楚。在这里，我们报道了S. agalactiae中血红素和原卟啉IX （PPIX）稳态的一个主要策略是基于两个新发现的操作子gbs1753 gbs1752（称为pefA pefB）和gbs1402 gbs1401 gbs1400（称为pefR pefC pefD）的调节流出系统，其中pef代表“卟啉调节流出”。体外和体内数据表明，marr超家族蛋白PefR是这两个操作子的抑制因子。血红素或PPIX均可减轻pefr介导的抑制。我们表明，细菌灭活的两个Pef外排系统显示累积敏感性这些卟啉，并提供证据，他们积累在细胞内。ΔpefR突变体，其中两个pef操作子都上调，血红素依赖性呼吸缺陷，毒力减弱。我们得出结论，这种新的外排调节控制了无乳链球菌细胞内血红素和PPIX的有效性，并且是其进行呼吸代谢和感染宿主的能力所必需的。许多细菌病原体的感染途径包括败血症，细菌暴露于富含血红素的血液中。血红素（铁原卟啉IX）通常被认为是细菌铁源。然而，虽然一些病原体不能生物合成血红素，但它们利用环境血红素来激活关键功能。例如，主要的新生儿病原体无乳链球菌与血红素的结合激活了一个潜在的呼吸链。呼吸代谢促进无乳链球菌在血液中的生长和存活，是产生毒力所必需的。虽然血红素在无乳链球菌行为中的重要性是有记录的，但它如何管理其细胞内血红素池仍然未知。我们发现了一种新的调控，称为“卟啉调节外排”的Pef，它调节无乳链球菌细胞内血红素和原卟啉IX的可用性。一个转录调控因子，PefR，抑制两个不同的外排转运操作子。调节因子介导的抑制可通过血红素或原卟啉IX减轻。重要的是，Pef外排转运蛋白的过度表达导致细胞内血红素不足，以及随之而来的呼吸和毒力缺陷。相反，当Pef外排转运体失活时，结果表明细胞内血红素和原卟啉IX的积累增加。这些研究指出，在细菌病原体中，调节外排运输系统的重要作用是维持细胞内血红素在足以刺激生长和促进感染的水平上。
Streptococcus agalactiae is a major neonatal pathogen whose infectious route involves septicemia. This pathogen does not synthesize heme, but scavenges it from blood to activate a respiration metabolism, which increases bacterial cell density and is required for full virulence. Factors that regulate heme pools in S. agalactiae are unknown. Here we report that one main strategy of heme and protoporphyrin IX (PPIX) homeostasis in S. agalactiae is based on a regulated system of efflux using two newly characterized operons, gbs1753 gbs1752 (called pefA pefB), and gbs1402 gbs1401 gbs1400 (called pefR pefC pefD), where pef stands for ‘porphyrin-regulated efflux’. In vitro and in vivo data show that PefR, a MarR-superfamily protein, is a repressor of both operons. Heme or PPIX both alleviate PefR-mediated repression. We show that bacteria inactivated for both Pef efflux systems display accrued sensitivity to these porphyrins, and give evidence that they accumulate intracellularly. The ΔpefR mutant, in which both pef operons are up-regulated, is defective for heme-dependent respiration, and attenuated for virulence. We conclude that this new efflux regulon controls intracellular heme and PPIX availability in S. agalactiae, and is needed for its capacity to undergo respiration metabolism, and to infect the host. The infectious route of numerous bacterial pathogens includes septicemia, where bacteria are exposed to heme-rich blood. Heme (iron protoporphyrin IX) is generally considered a bacterial iron source. However, while some pathogens do not biosynthesize heme, they use environmental heme to activate key functions. For example, incorporation of heme by the major neonatal pathogen Streptococcus agalactiae activates a latent respiration chain. Respiration metabolism stimulates S. agalactiae growth and survival in blood, and is needed for virulence. While the importance of heme in S. agalactiae behavior is documented, how it manages its intracellular heme pools remains unknown. We discovered a novel regulon, called Pef for “porphyrin-regulated efflux”, that modulates S. agalactiae intracellular availability of heme and protoporphyrin IX. A single transcriptional regulator, PefR, represses two distinct efflux transport operons. Regulator-mediated repression is alleviated by heme or protoporphyrin IX. Importantly, over-expression of Pef efflux transporters led to intracellular heme insufficiency, and consequent respiration and virulence defects. Inversely, when Pef efflux transporters were inactivated, results indicated an increased intracellular accumulation of heme and protoporphyrin IX. These studies point to the important role of regulated efflux transport systems in bacterial pathogens for maintaining intracellular heme at levels sufficient to stimulate growth and promote infection.
登录
查看更多内容
影响因子：
6.7
作者：
Friedman DB;Stauff DL;Pishchany G;Whitwell CW;Torres VJ;Skaar EP
通讯作者：
Skaar EP
影响因子：
64.8
作者：
Baughn, AD;Malamy, MH
通讯作者：
Malamy, MH
影响因子：
3.5
作者：
Gaillot, O;Poyart, C;Trieu-Cuot, P
通讯作者：
Trieu-Cuot, P
影响因子：
3.2
作者：
BISWAS, I;GRUSS, A;MAGUIN, E
通讯作者：
MAGUIN, E
影响因子：
3.1
作者：
Bibb, Lori A.;Kunkle, Carey A.;Schmitt, Michael P.
通讯作者：
Schmitt, Michael P.