铜绿假单胞菌致病因子抑制剂及喹诺酮信号分子介导的调节途径研究
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摘要
抗生素的使用使细菌感染类疾病得到了有效的控制,但随着耐药菌株的出现限制了人们治疗细菌感染性疾病的能力,感染性疾病再次对人类健康造成严重的威胁。铜绿假单胞菌(Pseudomonas aeruginosa, PA)是一种条件致病菌,是医院获得性感染的三大致病菌之一。它能引起各种不同的急性或慢性感染,特别是对于免疫功能缺陷或是患有慢性疾病的人群。抗生素的长期使用及滥用使铜绿假单胞菌对许多抗生素产生了严重的耐药性,这导致铜绿假单胞菌感染类疾病在临床治疗中面临了极大的困难。
细菌的致病力取决于细菌所产生的致病因子(或毒性因子)及其对宿主的损伤作用。致病菌通过释放毒性因子来破坏宿主细胞的正常生理功能,甚至导致宿主细胞的死亡。因此,通过抑制细菌感染宿主过程中所依赖的毒性因子,将可以抑制细菌的致病性,达到控制感染的目的。因此,对细菌致病途径及机理的研究,并在此基础上研发抗细菌致病性药物,已成为病原微生物和抗生素研究领域的一个全新的重要方向。
中药在我国具有数千年的历史,其防治感染性疾病的能力被人们所熟知。本课题以中药中“清热解毒”类药材为筛选对象,利用荧光素酶(Luciferase)基因luxCDABE为报道子连接于铜绿假单胞菌毒性相关基因的启动子之后,对致病因子基因进行标记,筛选并研究中药材中抗致病成分,探索其化学本质及其作用途径与机理。并在此基础上将黄芩苷的作用靶点—喹诺酮信号分子系统(Pseudomonas quinolone signal, PQS)对其所介导的致病因子的调节途径进行了深入的研究。
研究结果发现中药材黄芩粗提物和艾叶粗提物中存在抗铜绿假单胞菌致病性的成分,在对细菌的生长没有影响的条件下,黄芩粗提物可以明显的抑制铜绿假单胞菌毒性相关基因,其中包括群体感应系统(Quorum sensing, QS)基因lasI、lasR、rhlI和rhlR,Ⅲ型分泌系统基因exoS和运动相关基因filC的表达。而艾叶水提物可以抑制lasR、rhlI、 rhlR、exoS和filC的表达。且黄芩和艾叶粗提物均对铜绿假单胞菌丛动能力有明显的抑制作用。
进一步的研究发现,黄芩中含有的化学成分之一黄芩苷可以明显抑制铜绿假单胞菌毒性因子如Ⅲ型分泌系统、QS相关表型如鼠李糖脂、弹性蛋白酶以及细菌的丛动能力。结果表明黄芩苷很可能是黄芩抑制铜绿假单胞菌致病性的主要成分。
本课题以黄芩苷对Ⅲ型分泌系统中效应蛋白基因exoS的表达抑制为线索,进一步研究了黄芩苷对铜绿假单胞菌致病因子的作用途径和作用机理。在已知的致病因子全局调控系统的突变体中检测了黄芩苷对exoS表达抑制作用的变化,结果证明黄芩苷的作用依赖于PQS群体感应系统,它对致病因子的调节作用是通过这一途径来实现的。在PQS信号分子产生相关的pqsH基因突变体及调控蛋白PqsR (信号分子PQS的同源受体)突变菌株中,黄芩苷对exoS表达抑制作用消失。当PQS与PqsR蛋白共同存在的条件下,黄芩苷对Ⅲ型分泌系统的抑制作用即可恢复。但只有PQS信号分子前体HHQ与PqsR蛋白存在或者是只有PqsR蛋白本身存在的条件下,黄芩苷对Ⅲ型分泌系统的抑制作用不能恢复,这表明黄芩苷对Ⅲ型分泌系统的抑制作用是PQS与PqsR共同介导的。
研究还发现,黄芩苷可以使铜绿假单胞菌产生一个胞外未知物质。通过高效液相及质谱分析,初步确定了此物质的一些化学性质,此物质的极性性质类似于信号分子PQS,但并不是PQS信号分子。实验还发现铜绿假单胞菌产生此物质不需要PQS系统中的调控蛋白PqsR,推测此未知物质的产生可能与黄芩苷抗致病的作用机制有关。
利用体外小鼠细胞EMT6毒性、果蝇感染模型以及大鼠海藻包埋肺部感染模型,实验研究了黄芩苷对铜绿假单胞菌体内致病性的影响。细胞毒性实验以及果蝇感染实验,同时证明黄芩苷可以明显削弱铜绿假单胞菌PAO1的致病性。在进一步的动物肺炎模型实验中,通过大鼠肺组织病理分级、血清中炎症因子TNF-α含量以及肺组织内活菌计数等多项指标检测,结果证明黄芩苷除抑制铜绿假单胞菌致病因子外,可以减少机体炎症反应并加快大鼠对细菌的清除。这些结果表明黄芩苷是一个具有良好前景的、有效治疗铜绿假单胞菌感染的抗致病药物候选体。
针对黄芩苷作用靶点-PQS群体感应调节系统的进一步研究结果表明,此系统信号分子PQS对铜绿假单胞菌生物被膜的形成有重要的影响,同时对其丛动能力具有明显的抑制作用。本研究证明PQS对丛动能力的抑制作用不依赖于调控蛋白PqsR的存在；也与细菌鞭毛、菌毛的形成以及表面活性剂鼠李糖脂的产量变化无关。从实验结果发现铜绿假单胞菌的蹭行运动不受到PQS的调控,但却依赖于调控蛋白PqsR的存在。这一研究结果首次揭示了铜绿假单胞菌中喹诺酮信号分子对致病因子的调节是可以通过PqsR依赖和PqsR非依赖两种途径实现。与先前文献报道有所不同,本研究还发现PQS对铜绿假单胞菌生物被膜的促进与Las和Rhl系统的调节机制无关,而是依赖于GacAS/Rsm调控途径。研究还发现,PQS在突变体gacA中对铜绿假单胞菌丛动的抑制作用仍然存在,这表明了信号分子PQS对丛动能力的抑制和对生物被膜的增强作用是通过不同的机制来调控的。
Conventional antibiotics target viability; such antiniotics exert as elective pressure on pathogenic bacteria and hence cause the rise of drug resistance. Antibiotic resistance in pathogens limits our abilities to treat infectious diseases and has become a serious threat to human health. Pseudomonas aeruginosa (PA) is a Gram-negative opportunistic human pathogen. It is the third most common infectious agent in hospitals, and it can cause various acute and chronic infections in patients, especially those who are immuno-compromised or suffered other chronic diseases. With decades of conventional antibiotic treatment, many P. aeruginosa stains have become a multi-drug resistant, which leads to enormous difficulties in clinical treatment.
The ability of pathogens to cause disease depends on virulence factors, such as toxins, cytolysins or proteases which cause damage to host tissues. It is therefore plausible that bacterial infections can be treated or prevented by inhibitors of the bacterial virulence factors. Such inhibitors are a promising new kind of "antipathogenic"therapeutics.
Chinese herbs have been effectively used to treat infectious diseases for thousands of years. They represent a rich resource for antibacterial compound exploration. In this study, we screened for P. aeruginosa virulence factor inhibitors from Chinese herbs and investigated the pathways and molecular mechanisms of a potent inhibitor baicalin isolated from Scutellariae Radix. We constructed an array of virulence factor reporters with the virulence related gene promoters fused with promoterless luxCDABE cluster. Chinese herbs that are known for the functions of Qing Re Jie Du (i.e. treating symptoms resembling infections) were screened using this reporter array. In addition, the target of baicalin, i.e. the Pseudomonas quinolone signal system (PQS), was also investigated. The regulation of virulence factors by the PQS system and the corelation between the signal molecules and the transcriptional regulator PqsR (cognate receptor of PQS) in virulence regulation were investigated.
The results of our study revealed that the extract of medicinal plant Scutellariae Radix (the root of Scutellaria baicalensis Georgi) could inhibit the expression of Quorm sensing (QS) related genes including lasl, lasR, rhlI and rhlR, type Ⅲ secretion system (T3SS) effector gene exoS and flagella biosynthesis gene filC. We found Folium Artemisiae Argyi extract could inhibit the expression of QS lasR, rhlI, rhlR, exoS and filC in P. aeruginosa, while it had no influence on cell viability.
Further investigation indicate that baicalin, an flavonoid isolated from Scutellariae Radix significantly inhibited a range of important virulence factors in P. aeruginosa such as the Type III secretion system (T3SS), swarming motility and the production of rhamnolipid and elastase, suggesting that baicalin was the active anti-virulence component in the medicinal plant Scutellariae Radix.
Based on the observation that baicalin repressed the expression of T3SS effector gene exoS, we investigated the mechanism of baicalin inhibition on virulence exoS as a reporter. The exoS inhibition by baicalin was examined in the mutants of global regulatory system which are known controlling virulence factors in P. aeruginosa. The results demonstrated that PQS system is the target regulatory pathway through which baicalin excerted its inhibitory activity against virulence factors. Baicalin had no impact on exoS expression in the pqsH and pqsR mutants which are deficient in the PQS production and lack of regulatory protein PqsR (cognate receptor of PQS) respectively. The inhibition of exoS expression by baicalin was restored in the presence of PQS and PqsR, but not by the PQS precursor HHQ and PqsR or PqsR alone. The results demonstrated that the inhibition activity on the T3SS by baicalin is dependent on the PQS and its cognate receptor PqsR.
The activity of baicalin on the pathogenicity of P. aeruginosa was further tested using in vitro EMT6cells, fruit fly infection model, and the rat lung alginate-bead infection model. The result demonstrated that baicalin reduced the cellular toxicity of PAO1on the mammalian cell and attenuated its in vivo pathogenicity in the fly infection model. Moreover, the results using the rat pulmonary infection model demonstrated that baicalin reduced the inflammatory response and enhanced bacterial clearance by the host. These results suggest that baicalin is apromissing antipathogenic drug candidate for treating P. aeruginosa infections.
Study of the baicalin target-the PQS system showed that PQS stsyem is an important for P. aeruginosa motility and biofilm formation. We demonstrated that PQS molecules repressed the swarming motility of P. aeruginosa PAO1, and such regulation was independent on its cognate receptor PqsR but was not related to changes of the flagella, type IV pili or the production of the surface-wetting agent rhamnolipid surfactants. While PQS molecules did not affect twitching motility in PAO1, a pqsR deletion abolished twitching motility, indicating pqsR is required for twitching motility. The result for the first time revealed the distinct PqsR-dependent and PqsR-independent functions of PQS molecules. Our results also indicated that the enhancement of biofilm formation by PQS, at least partially, depended on the GacAS/Rsm regulatory pathway whereas without affecting the Las or Rhl QS systems. However, PQS still inhibited swarming motility in gacA mutant. It is likely that the effect of PQS on swarming motility and biofilm formation were exerted through different pathways.
细菌的致病力取决于细菌所产生的致病因子(或毒性因子)及其对宿主的损伤作用。致病菌通过释放毒性因子来破坏宿主细胞的正常生理功能,甚至导致宿主细胞的死亡。因此,通过抑制细菌感染宿主过程中所依赖的毒性因子,将可以抑制细菌的致病性,达到控制感染的目的。因此,对细菌致病途径及机理的研究,并在此基础上研发抗细菌致病性药物,已成为病原微生物和抗生素研究领域的一个全新的重要方向。
中药在我国具有数千年的历史,其防治感染性疾病的能力被人们所熟知。本课题以中药中“清热解毒”类药材为筛选对象,利用荧光素酶(Luciferase)基因luxCDABE为报道子连接于铜绿假单胞菌毒性相关基因的启动子之后,对致病因子基因进行标记,筛选并研究中药材中抗致病成分,探索其化学本质及其作用途径与机理。并在此基础上将黄芩苷的作用靶点—喹诺酮信号分子系统(Pseudomonas quinolone signal, PQS)对其所介导的致病因子的调节途径进行了深入的研究。
研究结果发现中药材黄芩粗提物和艾叶粗提物中存在抗铜绿假单胞菌致病性的成分,在对细菌的生长没有影响的条件下,黄芩粗提物可以明显的抑制铜绿假单胞菌毒性相关基因,其中包括群体感应系统(Quorum sensing, QS)基因lasI、lasR、rhlI和rhlR,Ⅲ型分泌系统基因exoS和运动相关基因filC的表达。而艾叶水提物可以抑制lasR、rhlI、 rhlR、exoS和filC的表达。且黄芩和艾叶粗提物均对铜绿假单胞菌丛动能力有明显的抑制作用。
进一步的研究发现,黄芩中含有的化学成分之一黄芩苷可以明显抑制铜绿假单胞菌毒性因子如Ⅲ型分泌系统、QS相关表型如鼠李糖脂、弹性蛋白酶以及细菌的丛动能力。结果表明黄芩苷很可能是黄芩抑制铜绿假单胞菌致病性的主要成分。
本课题以黄芩苷对Ⅲ型分泌系统中效应蛋白基因exoS的表达抑制为线索,进一步研究了黄芩苷对铜绿假单胞菌致病因子的作用途径和作用机理。在已知的致病因子全局调控系统的突变体中检测了黄芩苷对exoS表达抑制作用的变化,结果证明黄芩苷的作用依赖于PQS群体感应系统,它对致病因子的调节作用是通过这一途径来实现的。在PQS信号分子产生相关的pqsH基因突变体及调控蛋白PqsR (信号分子PQS的同源受体)突变菌株中,黄芩苷对exoS表达抑制作用消失。当PQS与PqsR蛋白共同存在的条件下,黄芩苷对Ⅲ型分泌系统的抑制作用即可恢复。但只有PQS信号分子前体HHQ与PqsR蛋白存在或者是只有PqsR蛋白本身存在的条件下,黄芩苷对Ⅲ型分泌系统的抑制作用不能恢复,这表明黄芩苷对Ⅲ型分泌系统的抑制作用是PQS与PqsR共同介导的。
研究还发现,黄芩苷可以使铜绿假单胞菌产生一个胞外未知物质。通过高效液相及质谱分析,初步确定了此物质的一些化学性质,此物质的极性性质类似于信号分子PQS,但并不是PQS信号分子。实验还发现铜绿假单胞菌产生此物质不需要PQS系统中的调控蛋白PqsR,推测此未知物质的产生可能与黄芩苷抗致病的作用机制有关。
利用体外小鼠细胞EMT6毒性、果蝇感染模型以及大鼠海藻包埋肺部感染模型,实验研究了黄芩苷对铜绿假单胞菌体内致病性的影响。细胞毒性实验以及果蝇感染实验,同时证明黄芩苷可以明显削弱铜绿假单胞菌PAO1的致病性。在进一步的动物肺炎模型实验中,通过大鼠肺组织病理分级、血清中炎症因子TNF-α含量以及肺组织内活菌计数等多项指标检测,结果证明黄芩苷除抑制铜绿假单胞菌致病因子外,可以减少机体炎症反应并加快大鼠对细菌的清除。这些结果表明黄芩苷是一个具有良好前景的、有效治疗铜绿假单胞菌感染的抗致病药物候选体。
针对黄芩苷作用靶点-PQS群体感应调节系统的进一步研究结果表明,此系统信号分子PQS对铜绿假单胞菌生物被膜的形成有重要的影响,同时对其丛动能力具有明显的抑制作用。本研究证明PQS对丛动能力的抑制作用不依赖于调控蛋白PqsR的存在；也与细菌鞭毛、菌毛的形成以及表面活性剂鼠李糖脂的产量变化无关。从实验结果发现铜绿假单胞菌的蹭行运动不受到PQS的调控,但却依赖于调控蛋白PqsR的存在。这一研究结果首次揭示了铜绿假单胞菌中喹诺酮信号分子对致病因子的调节是可以通过PqsR依赖和PqsR非依赖两种途径实现。与先前文献报道有所不同,本研究还发现PQS对铜绿假单胞菌生物被膜的促进与Las和Rhl系统的调节机制无关,而是依赖于GacAS/Rsm调控途径。研究还发现,PQS在突变体gacA中对铜绿假单胞菌丛动的抑制作用仍然存在,这表明了信号分子PQS对丛动能力的抑制和对生物被膜的增强作用是通过不同的机制来调控的。
Conventional antibiotics target viability; such antiniotics exert as elective pressure on pathogenic bacteria and hence cause the rise of drug resistance. Antibiotic resistance in pathogens limits our abilities to treat infectious diseases and has become a serious threat to human health. Pseudomonas aeruginosa (PA) is a Gram-negative opportunistic human pathogen. It is the third most common infectious agent in hospitals, and it can cause various acute and chronic infections in patients, especially those who are immuno-compromised or suffered other chronic diseases. With decades of conventional antibiotic treatment, many P. aeruginosa stains have become a multi-drug resistant, which leads to enormous difficulties in clinical treatment.
The ability of pathogens to cause disease depends on virulence factors, such as toxins, cytolysins or proteases which cause damage to host tissues. It is therefore plausible that bacterial infections can be treated or prevented by inhibitors of the bacterial virulence factors. Such inhibitors are a promising new kind of "antipathogenic"therapeutics.
Chinese herbs have been effectively used to treat infectious diseases for thousands of years. They represent a rich resource for antibacterial compound exploration. In this study, we screened for P. aeruginosa virulence factor inhibitors from Chinese herbs and investigated the pathways and molecular mechanisms of a potent inhibitor baicalin isolated from Scutellariae Radix. We constructed an array of virulence factor reporters with the virulence related gene promoters fused with promoterless luxCDABE cluster. Chinese herbs that are known for the functions of Qing Re Jie Du (i.e. treating symptoms resembling infections) were screened using this reporter array. In addition, the target of baicalin, i.e. the Pseudomonas quinolone signal system (PQS), was also investigated. The regulation of virulence factors by the PQS system and the corelation between the signal molecules and the transcriptional regulator PqsR (cognate receptor of PQS) in virulence regulation were investigated.
The results of our study revealed that the extract of medicinal plant Scutellariae Radix (the root of Scutellaria baicalensis Georgi) could inhibit the expression of Quorm sensing (QS) related genes including lasl, lasR, rhlI and rhlR, type Ⅲ secretion system (T3SS) effector gene exoS and flagella biosynthesis gene filC. We found Folium Artemisiae Argyi extract could inhibit the expression of QS lasR, rhlI, rhlR, exoS and filC in P. aeruginosa, while it had no influence on cell viability.
Further investigation indicate that baicalin, an flavonoid isolated from Scutellariae Radix significantly inhibited a range of important virulence factors in P. aeruginosa such as the Type III secretion system (T3SS), swarming motility and the production of rhamnolipid and elastase, suggesting that baicalin was the active anti-virulence component in the medicinal plant Scutellariae Radix.
Based on the observation that baicalin repressed the expression of T3SS effector gene exoS, we investigated the mechanism of baicalin inhibition on virulence exoS as a reporter. The exoS inhibition by baicalin was examined in the mutants of global regulatory system which are known controlling virulence factors in P. aeruginosa. The results demonstrated that PQS system is the target regulatory pathway through which baicalin excerted its inhibitory activity against virulence factors. Baicalin had no impact on exoS expression in the pqsH and pqsR mutants which are deficient in the PQS production and lack of regulatory protein PqsR (cognate receptor of PQS) respectively. The inhibition of exoS expression by baicalin was restored in the presence of PQS and PqsR, but not by the PQS precursor HHQ and PqsR or PqsR alone. The results demonstrated that the inhibition activity on the T3SS by baicalin is dependent on the PQS and its cognate receptor PqsR.
The activity of baicalin on the pathogenicity of P. aeruginosa was further tested using in vitro EMT6cells, fruit fly infection model, and the rat lung alginate-bead infection model. The result demonstrated that baicalin reduced the cellular toxicity of PAO1on the mammalian cell and attenuated its in vivo pathogenicity in the fly infection model. Moreover, the results using the rat pulmonary infection model demonstrated that baicalin reduced the inflammatory response and enhanced bacterial clearance by the host. These results suggest that baicalin is apromissing antipathogenic drug candidate for treating P. aeruginosa infections.
Study of the baicalin target-the PQS system showed that PQS stsyem is an important for P. aeruginosa motility and biofilm formation. We demonstrated that PQS molecules repressed the swarming motility of P. aeruginosa PAO1, and such regulation was independent on its cognate receptor PqsR but was not related to changes of the flagella, type IV pili or the production of the surface-wetting agent rhamnolipid surfactants. While PQS molecules did not affect twitching motility in PAO1, a pqsR deletion abolished twitching motility, indicating pqsR is required for twitching motility. The result for the first time revealed the distinct PqsR-dependent and PqsR-independent functions of PQS molecules. Our results also indicated that the enhancement of biofilm formation by PQS, at least partially, depended on the GacAS/Rsm regulatory pathway whereas without affecting the Las or Rhl QS systems. However, PQS still inhibited swarming motility in gacA mutant. It is likely that the effect of PQS on swarming motility and biofilm formation were exerted through different pathways.
引文
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