病原细菌溶藻弧菌和铜绿假单胞菌中致病相关系统的调控机制
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摘要
溶藻弧菌(Vibrio alginolyticus)是一种重要的动物致病菌,弧菌病暴发可以引起海水养殖动物的高死亡率,在欧洲和南亚等地导致重大的经济损失。该菌黏附宿主表面,形成细胞被膜,具有产生如外毒素碱性丝氨酸蛋白酶(Asp)和铁载体等胞外产物的能力。这些毒力机制与其致病性密切相关。
病原菌主要依赖多种分泌系统分泌的胞外蛋白的活性来利用养分、侵染宿主和适应环境。第六型分泌系统(T6SS)是一种新发现的、保守的细菌蛋白转运系统,在革兰氏阴性细菌中受到严谨的调控。在溶藻弧菌中存在两套T6SS基因簇(T6SSVA1和T6SSVA2),可以编码T6SS标志蛋白Hcp.VgrG以及IcmF,还包括丝氨酸-苏氨酸激酶／磷酸酶(PpkA和PppA)。多种与T6SS相关的细菌生理现象已经被报道,但是其内在机制尚不清楚。本研究发现T6SS的标志蛋白溶血素共调蛋白(Hcp1)的表达受到严谨的调控。进一步的实验发现,Hcp1的表达具有生长依赖性,在指数期时达到最高。群体感应系统(Quorum sensing, QS)中的调节因子LuxO和LuxR分别正调控和负调控该蛋白的表达。此外,可替换sigma因子RpoN以及由T6SSVA1基因簇中基因编码的增强子结合蛋白VasH也可以调控Hcp1的表达。T6SSVA1中不仅Hcp1基因,其他基因如icmFl、dpⅥ和vasA1也受到LuxR、RpoN和VasH的负调控。总之,本研究表明在溶藻弧菌中T6SS的表达受到了QS和可替换sigma因子的调控。
本研究第一次在溶藻弧菌中将T6SS分泌系统、QS以及与3’,5’-环二鸟苷酸(c-di-GMP)相关的多种毒力表型联系起来。两个T6SS基因簇的框内无标记缺失显示,T6SS的突变可以影响细菌的运动性、生物被膜形成、细胞聚集以及外毒素Asp的产生能力。ppkAl和pppA的缺失导致了Hcp1蛋白表达水平的改变,pppA的缺失促使分泌系统的开启,标志着这两个基因对于T6SS调控的重要作用。PppA/PpkA1通过控制胞内第二信使c-di-GMP的水平来控制多种表型的变化。更重要的是,PppA/PpkA1可以通过控制群体感应调节因子LuxR来调控Asp的表达,而在本实验室之前的研究中已经证明了LuxR对Asp的表达有正调控作用。全基因组转录谱分析结果表明,ppkA1和pppA缺失株中100多个基因的表达水平受到了显著的影响。以上结果表明,溶藻弧菌中T6SS的PppA/PpkAl介导调控多种表型,丰富了我们对新发现的T6SS系统的认识。
在胃肠道内,复杂的通信发生在定植的细菌与胃肠道细胞内。这些通信中包括了病原菌和宿主之间的通讯。条件致病菌铜绿假单胞菌(Pseudomonas aeruginosa)是众所周知的一种伤口和肺部感染的病原菌。它的毒力与其监控宿主化学信号的能力以及形成生物被膜黏附于表面的能力有关。本研究通过分析在环境压力下,由真核细胞水解ATP产生的、随后分泌到胃肠道内的信号分子腺苷对细菌病原性的影响,阐明了腺苷在调控铜绿假单胞菌的病原性中起到的关键作用。外源腺苷的添加抑制了铜绿假单胞菌形成生物被膜的能力,同时腺苷还可以通过抑制鼠李糖脂的产生来减弱细菌爬动的能力。由于腺苷的代谢物肌苷不会影响生物被膜的形成,并且由于腺苷代谢能力的丧失也不会影响细菌的表型,因此推测腺苷代谢物对于铜绿假单胞菌病原性的降低没有显著影响。腺苷还可以降低毒力因子的产生,例如绿脓菌素、弹性蛋白酶、胞外多糖、铁载体和假单胞菌喹诺酮信号,这些毒力因子的减少可以降低铜绿假单胞菌对秀丽隐杆线虫的侵染能力。为了探究腺苷降低铜绿假单胞菌的毒力机制,本研究采用全基因组转录分析方法,利用基因芯片技术,分析了腺苷添加对基因表达的影响。芯片结果显示腺苷的添加抑制了部分基因的表达,与在富含铁离子的环境中得到的结果相似。电泳迁移实验表明,铁相关基因的表达受到了腺苷的抑制,推测这是由于腺苷可以增强铁摄取调节因子Fur与pvdS和fagA等铁相关启动子的结合从而阻碍这些基因的转录。因此,腺苷作为一个跨界信号抑制某些铁摄取基因的表达,降低了铜绿假单胞菌的毒力。本研究意义在于提出了一个新的无毒的方法(添加腺苷)来抑制生物被膜的形成和降低毒力,并且对于最重要的毒力调节因子之一的Fur蛋白在铜绿假单胞菌中是如何受到控制的这一问题,提供了一个崭新的理解。
Vibrio alginolyticus is one of the important epizootic pathogens causing high mortality outbreaks of vibriosis in sea animals in farmed mariculture throughout Europe and South Asia, resulting in important economic losses. The abilities to adhere to the host surface, form biofilm and produce extracellular products such as the exotoxin alkaline serine protease (Asp) and siderophore have been suggested to be critically involved in virulence in this bacterium.
Bacterial pathogens mainly rely on the activity of proteins secreted by a variety of protein secretion systems for the nutrients utilization, pathogenesis and niche adaptation. The type VI secretion system (T6SS) is a newly-defined, conserved bacterial protein translocation system and is precisely regulated in Gram-negative bacterial pathogens. We show that two sets of T6SS gene clusters (T6SSVA1and T6SSVA2) reside in the genomes of V. alginolyticus, encoding T6SS hallmark proteins such as Hcp, VgrG, and IcmF as well as serine-threonine kinase/phosphatase PpkA and PppA. A wide range of T6SS-related bacterial processes have been described while their underlying mechanisms are not clear. In this study, expression of a haemolysin co-regulated protein (Hcpl), which is one of the hallmarks of T6SS, was found to be strictly regulated in V. alginolyticus. The expression of Hcpl was growth phase-dependent and the production of Hcpl reached a maximum in the exponential phase. The expression of Hcpl was positively and negatively regulated by quorum sensing (QS) regulators LuxO and LuxR, respectively. In addition, we observed that Hcpl expression required the alternative sigma factor RpoN and the enhancer binding protein (EBP) VasH, which is encoded in T6SSVA1gene cluster. Moreover, LuxR, RpoN, and VasH could positively regulate the expression of other T6SS genes. Taken together, it was demonstrated that the expression of T6SS in V. alginolyticus was under the regulation of quorum sensing and alternative sigma factor.
In this study, we identified a connection between the T6SS secretion/quorum sensing and various3',5'-cyclic diguanylic acid (c-di-GMP) associated virulence phenotypes in V. alginolyticus. In-frame deletion mutants were made in the two T6SS gene loci to show their influences on motility, biofilm formation, cell aggregation, and exotoxin Asp production. The deletion of ppkA1and pppA resulted in an obvious alteration in the expression and secretion of Hcp1, signifying their essential roles in regulation of T6SS. PppA/PpkAl controlled pleiotropic phenotypes through the modulation of intracellular levels of second messenger c-di-GMP. Moreover, PppA/PpkAl also regulated the expression of Asp through manipulation of the expression of the quorum sensing regulator LuxR, which positively regulates the extracellular protease expression. Whole genome transcriptional profiling of ppkAl and pppA deletion strains revealed that the expression levels of over100genes were significantly co-regulated. These results demonstrate new roles of T6SS mediated by PppA/PpkAl in controlling pleiotropic phenotypes and contribute to our understanding of the conserved T6SS.
In the gastrointestinal (GI) tract, complex communication occurs between the colonizing bacterial species and the cells of GI tract. This communication includes crosstalk between pathogens and the host. The opportunistic pathogen Pseudomonas aeruginosa is a well known wound and lung pathogen whose virulence is related to its abilities to monitor host chemical signals and to form communities of cells attached to surfaces known as biofilms. Here the breakdown product of ATP, adenosine, which is released into the GI tract by stressed eucaryotic cells, was found to play an important role in regulating the pathogenicity of P. aeruginosa. The addition of adenosine repressed P. aeruginosa biofilm formation and abolished bacterial swarming by preventing production of rhamnolipids. Since the adenosine metabolite, inosine, did not affect biofilm formation and a mutant unable to metabolize adenosine behaved like the wild-type strain, adenosine metabolism could be believed to be unrelated to the reduction of pathogenicity. Adenosine also reduces production of the virulence factors pyocyanin, elastase, EPS, siderophores, and the Pseudomonas quinolone signal which led to reduced virulence with Caenorhabditis elegans. To determine the mechanism by which adenosine reduces the virulence of P. aeruginosa, a whole-transcriptome analysis was conducted, and it was revealed that adenosine addition repressed genes similar to an iron-replete condition. DNA binding assays showed that adenosine repressed the iron-related genes through it increased the affinity of Fur for both the pvdS and fagA iron-related promoters. Therefore, adenosine decreases P. aeruginosa pathogenicity as an interkingdom signal by repressing genes related to iron acquisition. Significantly, this study provides a novel and nontoxic way (adenosine addition) to inhibit biofilm formation and virulence as well as an insight into how one of the most important virulence regulators is controlled.
病原菌主要依赖多种分泌系统分泌的胞外蛋白的活性来利用养分、侵染宿主和适应环境。第六型分泌系统(T6SS)是一种新发现的、保守的细菌蛋白转运系统,在革兰氏阴性细菌中受到严谨的调控。在溶藻弧菌中存在两套T6SS基因簇(T6SSVA1和T6SSVA2),可以编码T6SS标志蛋白Hcp.VgrG以及IcmF,还包括丝氨酸-苏氨酸激酶／磷酸酶(PpkA和PppA)。多种与T6SS相关的细菌生理现象已经被报道,但是其内在机制尚不清楚。本研究发现T6SS的标志蛋白溶血素共调蛋白(Hcp1)的表达受到严谨的调控。进一步的实验发现,Hcp1的表达具有生长依赖性,在指数期时达到最高。群体感应系统(Quorum sensing, QS)中的调节因子LuxO和LuxR分别正调控和负调控该蛋白的表达。此外,可替换sigma因子RpoN以及由T6SSVA1基因簇中基因编码的增强子结合蛋白VasH也可以调控Hcp1的表达。T6SSVA1中不仅Hcp1基因,其他基因如icmFl、dpⅥ和vasA1也受到LuxR、RpoN和VasH的负调控。总之,本研究表明在溶藻弧菌中T6SS的表达受到了QS和可替换sigma因子的调控。
本研究第一次在溶藻弧菌中将T6SS分泌系统、QS以及与3’,5’-环二鸟苷酸(c-di-GMP)相关的多种毒力表型联系起来。两个T6SS基因簇的框内无标记缺失显示,T6SS的突变可以影响细菌的运动性、生物被膜形成、细胞聚集以及外毒素Asp的产生能力。ppkAl和pppA的缺失导致了Hcp1蛋白表达水平的改变,pppA的缺失促使分泌系统的开启,标志着这两个基因对于T6SS调控的重要作用。PppA/PpkA1通过控制胞内第二信使c-di-GMP的水平来控制多种表型的变化。更重要的是,PppA/PpkA1可以通过控制群体感应调节因子LuxR来调控Asp的表达,而在本实验室之前的研究中已经证明了LuxR对Asp的表达有正调控作用。全基因组转录谱分析结果表明,ppkA1和pppA缺失株中100多个基因的表达水平受到了显著的影响。以上结果表明,溶藻弧菌中T6SS的PppA/PpkAl介导调控多种表型,丰富了我们对新发现的T6SS系统的认识。
在胃肠道内,复杂的通信发生在定植的细菌与胃肠道细胞内。这些通信中包括了病原菌和宿主之间的通讯。条件致病菌铜绿假单胞菌(Pseudomonas aeruginosa)是众所周知的一种伤口和肺部感染的病原菌。它的毒力与其监控宿主化学信号的能力以及形成生物被膜黏附于表面的能力有关。本研究通过分析在环境压力下,由真核细胞水解ATP产生的、随后分泌到胃肠道内的信号分子腺苷对细菌病原性的影响,阐明了腺苷在调控铜绿假单胞菌的病原性中起到的关键作用。外源腺苷的添加抑制了铜绿假单胞菌形成生物被膜的能力,同时腺苷还可以通过抑制鼠李糖脂的产生来减弱细菌爬动的能力。由于腺苷的代谢物肌苷不会影响生物被膜的形成,并且由于腺苷代谢能力的丧失也不会影响细菌的表型,因此推测腺苷代谢物对于铜绿假单胞菌病原性的降低没有显著影响。腺苷还可以降低毒力因子的产生,例如绿脓菌素、弹性蛋白酶、胞外多糖、铁载体和假单胞菌喹诺酮信号,这些毒力因子的减少可以降低铜绿假单胞菌对秀丽隐杆线虫的侵染能力。为了探究腺苷降低铜绿假单胞菌的毒力机制,本研究采用全基因组转录分析方法,利用基因芯片技术,分析了腺苷添加对基因表达的影响。芯片结果显示腺苷的添加抑制了部分基因的表达,与在富含铁离子的环境中得到的结果相似。电泳迁移实验表明,铁相关基因的表达受到了腺苷的抑制,推测这是由于腺苷可以增强铁摄取调节因子Fur与pvdS和fagA等铁相关启动子的结合从而阻碍这些基因的转录。因此,腺苷作为一个跨界信号抑制某些铁摄取基因的表达,降低了铜绿假单胞菌的毒力。本研究意义在于提出了一个新的无毒的方法(添加腺苷)来抑制生物被膜的形成和降低毒力,并且对于最重要的毒力调节因子之一的Fur蛋白在铜绿假单胞菌中是如何受到控制的这一问题,提供了一个崭新的理解。
Vibrio alginolyticus is one of the important epizootic pathogens causing high mortality outbreaks of vibriosis in sea animals in farmed mariculture throughout Europe and South Asia, resulting in important economic losses. The abilities to adhere to the host surface, form biofilm and produce extracellular products such as the exotoxin alkaline serine protease (Asp) and siderophore have been suggested to be critically involved in virulence in this bacterium.
Bacterial pathogens mainly rely on the activity of proteins secreted by a variety of protein secretion systems for the nutrients utilization, pathogenesis and niche adaptation. The type VI secretion system (T6SS) is a newly-defined, conserved bacterial protein translocation system and is precisely regulated in Gram-negative bacterial pathogens. We show that two sets of T6SS gene clusters (T6SSVA1and T6SSVA2) reside in the genomes of V. alginolyticus, encoding T6SS hallmark proteins such as Hcp, VgrG, and IcmF as well as serine-threonine kinase/phosphatase PpkA and PppA. A wide range of T6SS-related bacterial processes have been described while their underlying mechanisms are not clear. In this study, expression of a haemolysin co-regulated protein (Hcpl), which is one of the hallmarks of T6SS, was found to be strictly regulated in V. alginolyticus. The expression of Hcpl was growth phase-dependent and the production of Hcpl reached a maximum in the exponential phase. The expression of Hcpl was positively and negatively regulated by quorum sensing (QS) regulators LuxO and LuxR, respectively. In addition, we observed that Hcpl expression required the alternative sigma factor RpoN and the enhancer binding protein (EBP) VasH, which is encoded in T6SSVA1gene cluster. Moreover, LuxR, RpoN, and VasH could positively regulate the expression of other T6SS genes. Taken together, it was demonstrated that the expression of T6SS in V. alginolyticus was under the regulation of quorum sensing and alternative sigma factor.
In this study, we identified a connection between the T6SS secretion/quorum sensing and various3',5'-cyclic diguanylic acid (c-di-GMP) associated virulence phenotypes in V. alginolyticus. In-frame deletion mutants were made in the two T6SS gene loci to show their influences on motility, biofilm formation, cell aggregation, and exotoxin Asp production. The deletion of ppkA1and pppA resulted in an obvious alteration in the expression and secretion of Hcp1, signifying their essential roles in regulation of T6SS. PppA/PpkAl controlled pleiotropic phenotypes through the modulation of intracellular levels of second messenger c-di-GMP. Moreover, PppA/PpkAl also regulated the expression of Asp through manipulation of the expression of the quorum sensing regulator LuxR, which positively regulates the extracellular protease expression. Whole genome transcriptional profiling of ppkAl and pppA deletion strains revealed that the expression levels of over100genes were significantly co-regulated. These results demonstrate new roles of T6SS mediated by PppA/PpkAl in controlling pleiotropic phenotypes and contribute to our understanding of the conserved T6SS.
In the gastrointestinal (GI) tract, complex communication occurs between the colonizing bacterial species and the cells of GI tract. This communication includes crosstalk between pathogens and the host. The opportunistic pathogen Pseudomonas aeruginosa is a well known wound and lung pathogen whose virulence is related to its abilities to monitor host chemical signals and to form communities of cells attached to surfaces known as biofilms. Here the breakdown product of ATP, adenosine, which is released into the GI tract by stressed eucaryotic cells, was found to play an important role in regulating the pathogenicity of P. aeruginosa. The addition of adenosine repressed P. aeruginosa biofilm formation and abolished bacterial swarming by preventing production of rhamnolipids. Since the adenosine metabolite, inosine, did not affect biofilm formation and a mutant unable to metabolize adenosine behaved like the wild-type strain, adenosine metabolism could be believed to be unrelated to the reduction of pathogenicity. Adenosine also reduces production of the virulence factors pyocyanin, elastase, EPS, siderophores, and the Pseudomonas quinolone signal which led to reduced virulence with Caenorhabditis elegans. To determine the mechanism by which adenosine reduces the virulence of P. aeruginosa, a whole-transcriptome analysis was conducted, and it was revealed that adenosine addition repressed genes similar to an iron-replete condition. DNA binding assays showed that adenosine repressed the iron-related genes through it increased the affinity of Fur for both the pvdS and fagA iron-related promoters. Therefore, adenosine decreases P. aeruginosa pathogenicity as an interkingdom signal by repressing genes related to iron acquisition. Significantly, this study provides a novel and nontoxic way (adenosine addition) to inhibit biofilm formation and virulence as well as an insight into how one of the most important virulence regulators is controlled.
引文
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