分枝杆菌无机磷酸盐转运相关蛋白PhoY2生物学功能及致病机制研究
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摘要
由结核分枝杆菌(Mycobacterium tuberculosis, M. tuberculosis)感染所引起的结核病(Tuberculosis, TB)目前仍然是严重危害人类公共卫生安全的传染性疾病之一,每年在全球范围内造成近两百万人口死亡。只有大约5%-10%的人在感染M.tuberculosis后会在短时间内发展为活动性结核(Active TB);余下90%-95%被感染人群发展为对结核菌素纯蛋白衍生物(M.tuberculosis purified protein derivative, PPD)免疫学测试结果为阳性(M.tuberculosis感染证据)、但无任何临床症状的潜伏感染(Latent TB)。据世界卫生组织估计,全球有近1/3的人PPD测试结果为阳性,这近20亿人口的潜伏感染人群是活动性结核患者的重要病源。
结核病潜伏感染及发病的分子机理尚未研究清楚。在潜伏感染的状态下,细菌与宿主之间达成一种平衡：宿主的免疫系统不会完全清除细菌,细菌也不会迅速的增殖扩散而损害机体造成活动性疾病。宿主在感染细菌后会通过形成巨噬细胞吞噬溶酶体、低氧和营养缺陷的肉芽肿(Granuloma)等压力环境来控制细菌的增殖和传播,但M.tuberculosis能够通过各种机制适应所处环境的压力变化从而得以在机体内长期存活。一旦宿主的免疫系统受到损害,例如感染HIV(Human immunodeficiency virus)病毒或接受抗肿瘤坏死因子(Tumor Necrosis Factor alpha, TNF-a)抗体治疗,细菌就会重新活化增殖而致病。前期的研究利用体外的低氧、营养缺陷、一氧化氮等压力模型找出了细菌中许多参与这一适应过程的调控基因,例如对低氧环境的适应起主要作用的DosR Regulon、EHR基因等。
磷元素是构成生物体的必须元素。细菌在长期的进化过程中形成了复杂的无机磷酸盐转运系统Pho Regulon来调控磷元素的代谢和平衡。其中的关键组成部分是无机磷酸盐特异性转运系统(Phosphate specific transporter system, Pst system),在模式细菌大肠埃希杆菌(Escherichia coli, E.coli)中,Pst系统由胞膜外磷酸盐浓度感知蛋白PstS、胞膜通道蛋白PstA和]PstC、ATP结合蛋白PstB构成,共同调控细菌对胞外Pi的摄取。Pho Regulon主要由PhoR/PhoB双组分系统调控。在无机磷酸盐缺陷的环境下,PhoR蛋白会自磷酸化并将磷酸化基团传递给PhoP,以启动能激活Pho Regulon的基因应答。当细菌所处的外界环境无机磷酸盐过量时,PhoR又能行使磷酸酶的功能对磷酸化的PhoB蛋白进行去磷酸化以中止相关基因的激活。PhoU是位于胞膜内的调控蛋白,对PhoB磷酸化蛋白的去磷酸化以及Pho Regulon在富集的无机磷酸盐环境中的调控至关重要。PhoU蛋白的详细调控机制尚未明晰,结构生物学上证据推测它可能直接与PhoR/PhoB蛋白相互作用并影响其功能。
在M. tuberculosis中有两个PhoU蛋白的同源成分：PhoY1和(Rv3301c)PhoY2(Rv0821c),二者在氨基酸序列上与大肠埃希杆菌的同源系分别为40%和44%。前期的研究通过鉴定PhoY1和PhoY2蛋白突变的M. tuberculosis在抗生素压力和动物感染模型体内压力情况下持续性感染形成的能力发现PhoY2与PhoU具有相同的表型。PhoY2蛋白调控这些表型形成的机制尚未有研究报道。我们通过筛选分枝杆菌研究的模式细菌——海分枝杆菌(Mycobacterium marinum, M.marinum)的转座子插入突变库,得到了PhoU同源蛋白PhoY2的突变菌株phoY2::Tn。我们的研究发现：M. marinum中phoY2基因的插入失活导致胞内poly Pi浓度上调；突变菌株胞内ATP的含量也随着poly Pi量的上调而增加；处于poly Pi和ATP代谢失调的phoY2::Tn菌株不仅对体外高磷酸盐浓度更为敏感,在细胞壁裂解剂十二烷基磺酸钠(SDS)、营养缺陷、抗生素等环境压力的处理下,其生存能力均降低；此外,体外低氧模型的研究结果也发现phoY2::Tn对低氧环境的适应过程、从低氧状态下的休眠期复苏受到了影响。基于这些工作基础和相关研究背景,我们提出：PhoY2蛋白在维持分枝杆菌的代谢平衡和对环境压力的应答中发挥重要的作用。(论文第一章)
结核病由潜伏感染到发病是一个复杂的、由宿主与M.tuberculosis相互作用的过程。诸多宿主因素参与了对潜伏感染的调控。在本论文的第二部份,我们研究了microRNA (miRNA)在这一过程中的调控作用。miRNA是一类22bp左右的内源性RNA片段,能通过与靶基因mRNA结合并降解mRNA的的机制来抑制靶基因的表达,从而在哺乳动物和植物的转录后调控中发挥重要的作用。目前,在人类miRNA数据库中已经有约1000余种miRNA的详细信息记录。这使得miRNA能调控一些重要的生物学过程如细胞发育、分化、凋亡、新陈代谢、抵御病毒侵染、肿瘤发生等。miRNA同样可以通过调控免疫细胞的发育和分化来调控固有免疫和获得性免疫系统对病原体入侵的免疫反应。前期的临床研究发现miRNA可以在多种癌症的诊断、预后等过程中做为生物标记(Biomarker)发挥作用。与之相比,在感染性疾病,特别是细菌感染性疾病中miRNA的调控和临床作用的研究仍然很少。我们使用微芯片(Microarray)技术比较了活动性结核患者、结核潜伏感染人群和健康人群外周血单核细胞miRNA的表达谱,找出了在三组人群中表达有差异的miRNA并使用实时荧光实时定量PCR方法予以验证。根据这些miRNA在数据库中记录的靶基因信息,我们构建了活动性结核患者和潜伏感染人群之间差异miRNA的调控网络。我们的研究对miRNA介导的结核病潜伏感染调控机制有了新的认识。(论文第二章)
Tuberculosis (TB), caused by Mycobacterium tuberculosis (M.tuberculosis), causes approximately2million deaths annually and remains a threat to global health. Approximately5to10%of M.tuberculosis-infected individual develops active TB at some stage in their life. The remaining,90to95%infected people remain asymptomatic, carrying so-called latent TB infection (LTBI), which is defined solely by the evidence of immunological sensitization to mycobacterial proteins (M tuberculosis purified protein derivative, PPD) in the absence of clinical signs and symptoms of active disease. The World Health Organization estimates that nearly one third of the world population is PPD+. This vast reservoir of LTBI-infected individuals is a constant source of disease caused by reactivation.
The exact underlying mechanisms of LTBI and its transition to active TB remain elusive. LTBI rely on an equilibrium in which the host is able to control the infection but does not completely eradicate the bacteria. The host could form several in vivo environmental stresses include phagocytic vacuoles of macrophages, hypoxic and nutrient-limited environments within granulomas, as well as oxygen-rich alveolar airspaces to control the replication and spread of bacteria.However, some bacteria could adapt to such diverse conditions by altering its physiology in response to changes in the environment therefore survive in a phenotype called dormancy for a long period. Immunosuppressants such as HIV infection or antitumor necrosis factor (TNF) treatment for rheumatoid arthritis may lead to the reactivation of these bacteria. Studies of M tuberculosis response to several stress conditions including hypoxia, nutrient deprivation, nitric oxide treatment and growth in acidic media have been described and genes induced by certain stress conditions such as the DosR regulon and EHR genes in response to hypoxia have been identified.
Phosphate is an essential nutrient for cell functions and life. Bacteria employ a sophisticated system, encoded by the Pho regulon, to manage inorganic phosphate (Pi) acquisition and metabolism. A key component of the Pho regulon is the ABC-type phosphate specific transporter (Pst) system consisting of PstSCAB. PstS is a periplasmic protein that binds Pi with high affinity, PstC and PstA are cytoplasmic membrane transporters for Pi translocation into the cytosol, and PstB is an ATPase that provides energy for the transporter. The Pho regulon is controlled by the PhoR/PhoB two-component regulatory system. Under Pi limitation, PhoR is autophosphorylated and transfers a phosphoryl group to PhoB, which in turn activates target genes including the Pho regulon. When Pi is in excess, the activation is interrupted by PhoR acting as a phosphatase on phosphor-PhoB. PhoU, a peripheral membrane protein, is also required for dephosphorylation of PhoB and is essential for repression of Pho regulon under Pi rich condition. The precise mechanism of PhoU action is unknown, but it may interact with PhoR/PhoB proteins and interfere with their functions.
There are two PhoU homologues in M.tuberculosis, PhoYl (Rv3301c) and PhoY2(RvO821c) which share40%and44%homology to E. coli PhoU. Previous studies showed that disruption of phoY2but not phoY1in M. tuberculosis resulted in increased susceptibility to antibiotics and reduced persistence of the bacterium in mice. The persistence phenotype of phoY2mutant is similar to that of phoU mutant of E. coli, suggesting that PhoY2is the functional homolog of PhoU. However, the underlying molecular mechanisms for the observed phenotypes associated with phoY2mutation in mycobacteria remain unknown. In the first part of this study, we characterized a transposon inactivated phoY2mutant of Mycobacterium marinum (M marinum). We found that the disruption of phoY2resulted in elevated levels of intracellular poly-Pi and ATP. The expression of phoY2was induced by environmental stress conditions and the phoY2::Tn mutant exhibited increased sensitivity to SDS, antibiotics and excessive levels of Pi. We also investigated the phenotypes of the phoY2::Tn mutant under hypoxia-induced dormancy. Taken together, our results indicate that PhoY2is required for maintaining metabolic homeostasis and adaption to environmental stress conditions (Part1).
The transition of latent to active TB is a complex process, which depends on the interaction between host and mycobacterium. In the second part of this work, we investigate the regulated role of microRNA (miRNA) in this process. miRNAs are endogenous,22-nucleotide RNAs that play important regulatory roles in animals and plants by targeting mRNAs for cleavage or translational repression. There are currently1,000human miRNAs sequences listed in the miRNA registry which may target about60%of all mammalian genes [http://www.mirbase.org/], indicating that these small molecules play fundamental and global functions in human biology, including development, differentiation, apoptosis, metabolism, viral infection, and cancer. MiRNAs also modulate the innate and adaptive immune responses to pathogens by affecting mammalian immune cell differentiation and the development of diseases of immunological origin.The clinical application of miRNAs as diagnostic or prognostic biomarkers has already been demonstrated in various types of cancers. However, compared to their well-known role in cancer, the role of miRNAs in susceptibility and resistance to infectious disease, especially those of bacterial origin, is still poorly understood. We compared the miRNA expression profiles of PBMCs from patients with active TB, subjects with LTBI, and healthy controls in order to test the hypothesis that candidate miRNAs regulate the transition from LTBI to active TB. We used a miRNA microarray chip containing,960probes to identify the differently expressed miRNAs, and performed realtime quantitative polymerase chain reaction (qPCR) for confirmation. The putative regulatory network of miRNAs that were differentially expressed in the samples from active TB and LTBI individuals was constructed based on predicted target genes and previously published genome-wide transcriptional profiles. Our study provides a greater understanding of the role of miRNAsmediated regulated networks in the transition from latent to active TB (Part
结核病潜伏感染及发病的分子机理尚未研究清楚。在潜伏感染的状态下,细菌与宿主之间达成一种平衡：宿主的免疫系统不会完全清除细菌,细菌也不会迅速的增殖扩散而损害机体造成活动性疾病。宿主在感染细菌后会通过形成巨噬细胞吞噬溶酶体、低氧和营养缺陷的肉芽肿(Granuloma)等压力环境来控制细菌的增殖和传播,但M.tuberculosis能够通过各种机制适应所处环境的压力变化从而得以在机体内长期存活。一旦宿主的免疫系统受到损害,例如感染HIV(Human immunodeficiency virus)病毒或接受抗肿瘤坏死因子(Tumor Necrosis Factor alpha, TNF-a)抗体治疗,细菌就会重新活化增殖而致病。前期的研究利用体外的低氧、营养缺陷、一氧化氮等压力模型找出了细菌中许多参与这一适应过程的调控基因,例如对低氧环境的适应起主要作用的DosR Regulon、EHR基因等。
磷元素是构成生物体的必须元素。细菌在长期的进化过程中形成了复杂的无机磷酸盐转运系统Pho Regulon来调控磷元素的代谢和平衡。其中的关键组成部分是无机磷酸盐特异性转运系统(Phosphate specific transporter system, Pst system),在模式细菌大肠埃希杆菌(Escherichia coli, E.coli)中,Pst系统由胞膜外磷酸盐浓度感知蛋白PstS、胞膜通道蛋白PstA和]PstC、ATP结合蛋白PstB构成,共同调控细菌对胞外Pi的摄取。Pho Regulon主要由PhoR/PhoB双组分系统调控。在无机磷酸盐缺陷的环境下,PhoR蛋白会自磷酸化并将磷酸化基团传递给PhoP,以启动能激活Pho Regulon的基因应答。当细菌所处的外界环境无机磷酸盐过量时,PhoR又能行使磷酸酶的功能对磷酸化的PhoB蛋白进行去磷酸化以中止相关基因的激活。PhoU是位于胞膜内的调控蛋白,对PhoB磷酸化蛋白的去磷酸化以及Pho Regulon在富集的无机磷酸盐环境中的调控至关重要。PhoU蛋白的详细调控机制尚未明晰,结构生物学上证据推测它可能直接与PhoR/PhoB蛋白相互作用并影响其功能。
在M. tuberculosis中有两个PhoU蛋白的同源成分：PhoY1和(Rv3301c)PhoY2(Rv0821c),二者在氨基酸序列上与大肠埃希杆菌的同源系分别为40%和44%。前期的研究通过鉴定PhoY1和PhoY2蛋白突变的M. tuberculosis在抗生素压力和动物感染模型体内压力情况下持续性感染形成的能力发现PhoY2与PhoU具有相同的表型。PhoY2蛋白调控这些表型形成的机制尚未有研究报道。我们通过筛选分枝杆菌研究的模式细菌——海分枝杆菌(Mycobacterium marinum, M.marinum)的转座子插入突变库,得到了PhoU同源蛋白PhoY2的突变菌株phoY2::Tn。我们的研究发现：M. marinum中phoY2基因的插入失活导致胞内poly Pi浓度上调；突变菌株胞内ATP的含量也随着poly Pi量的上调而增加；处于poly Pi和ATP代谢失调的phoY2::Tn菌株不仅对体外高磷酸盐浓度更为敏感,在细胞壁裂解剂十二烷基磺酸钠(SDS)、营养缺陷、抗生素等环境压力的处理下,其生存能力均降低；此外,体外低氧模型的研究结果也发现phoY2::Tn对低氧环境的适应过程、从低氧状态下的休眠期复苏受到了影响。基于这些工作基础和相关研究背景,我们提出：PhoY2蛋白在维持分枝杆菌的代谢平衡和对环境压力的应答中发挥重要的作用。(论文第一章)
结核病由潜伏感染到发病是一个复杂的、由宿主与M.tuberculosis相互作用的过程。诸多宿主因素参与了对潜伏感染的调控。在本论文的第二部份,我们研究了microRNA (miRNA)在这一过程中的调控作用。miRNA是一类22bp左右的内源性RNA片段,能通过与靶基因mRNA结合并降解mRNA的的机制来抑制靶基因的表达,从而在哺乳动物和植物的转录后调控中发挥重要的作用。目前,在人类miRNA数据库中已经有约1000余种miRNA的详细信息记录。这使得miRNA能调控一些重要的生物学过程如细胞发育、分化、凋亡、新陈代谢、抵御病毒侵染、肿瘤发生等。miRNA同样可以通过调控免疫细胞的发育和分化来调控固有免疫和获得性免疫系统对病原体入侵的免疫反应。前期的临床研究发现miRNA可以在多种癌症的诊断、预后等过程中做为生物标记(Biomarker)发挥作用。与之相比,在感染性疾病,特别是细菌感染性疾病中miRNA的调控和临床作用的研究仍然很少。我们使用微芯片(Microarray)技术比较了活动性结核患者、结核潜伏感染人群和健康人群外周血单核细胞miRNA的表达谱,找出了在三组人群中表达有差异的miRNA并使用实时荧光实时定量PCR方法予以验证。根据这些miRNA在数据库中记录的靶基因信息,我们构建了活动性结核患者和潜伏感染人群之间差异miRNA的调控网络。我们的研究对miRNA介导的结核病潜伏感染调控机制有了新的认识。(论文第二章)
Tuberculosis (TB), caused by Mycobacterium tuberculosis (M.tuberculosis), causes approximately2million deaths annually and remains a threat to global health. Approximately5to10%of M.tuberculosis-infected individual develops active TB at some stage in their life. The remaining,90to95%infected people remain asymptomatic, carrying so-called latent TB infection (LTBI), which is defined solely by the evidence of immunological sensitization to mycobacterial proteins (M tuberculosis purified protein derivative, PPD) in the absence of clinical signs and symptoms of active disease. The World Health Organization estimates that nearly one third of the world population is PPD+. This vast reservoir of LTBI-infected individuals is a constant source of disease caused by reactivation.
The exact underlying mechanisms of LTBI and its transition to active TB remain elusive. LTBI rely on an equilibrium in which the host is able to control the infection but does not completely eradicate the bacteria. The host could form several in vivo environmental stresses include phagocytic vacuoles of macrophages, hypoxic and nutrient-limited environments within granulomas, as well as oxygen-rich alveolar airspaces to control the replication and spread of bacteria.However, some bacteria could adapt to such diverse conditions by altering its physiology in response to changes in the environment therefore survive in a phenotype called dormancy for a long period. Immunosuppressants such as HIV infection or antitumor necrosis factor (TNF) treatment for rheumatoid arthritis may lead to the reactivation of these bacteria. Studies of M tuberculosis response to several stress conditions including hypoxia, nutrient deprivation, nitric oxide treatment and growth in acidic media have been described and genes induced by certain stress conditions such as the DosR regulon and EHR genes in response to hypoxia have been identified.
Phosphate is an essential nutrient for cell functions and life. Bacteria employ a sophisticated system, encoded by the Pho regulon, to manage inorganic phosphate (Pi) acquisition and metabolism. A key component of the Pho regulon is the ABC-type phosphate specific transporter (Pst) system consisting of PstSCAB. PstS is a periplasmic protein that binds Pi with high affinity, PstC and PstA are cytoplasmic membrane transporters for Pi translocation into the cytosol, and PstB is an ATPase that provides energy for the transporter. The Pho regulon is controlled by the PhoR/PhoB two-component regulatory system. Under Pi limitation, PhoR is autophosphorylated and transfers a phosphoryl group to PhoB, which in turn activates target genes including the Pho regulon. When Pi is in excess, the activation is interrupted by PhoR acting as a phosphatase on phosphor-PhoB. PhoU, a peripheral membrane protein, is also required for dephosphorylation of PhoB and is essential for repression of Pho regulon under Pi rich condition. The precise mechanism of PhoU action is unknown, but it may interact with PhoR/PhoB proteins and interfere with their functions.
There are two PhoU homologues in M.tuberculosis, PhoYl (Rv3301c) and PhoY2(RvO821c) which share40%and44%homology to E. coli PhoU. Previous studies showed that disruption of phoY2but not phoY1in M. tuberculosis resulted in increased susceptibility to antibiotics and reduced persistence of the bacterium in mice. The persistence phenotype of phoY2mutant is similar to that of phoU mutant of E. coli, suggesting that PhoY2is the functional homolog of PhoU. However, the underlying molecular mechanisms for the observed phenotypes associated with phoY2mutation in mycobacteria remain unknown. In the first part of this study, we characterized a transposon inactivated phoY2mutant of Mycobacterium marinum (M marinum). We found that the disruption of phoY2resulted in elevated levels of intracellular poly-Pi and ATP. The expression of phoY2was induced by environmental stress conditions and the phoY2::Tn mutant exhibited increased sensitivity to SDS, antibiotics and excessive levels of Pi. We also investigated the phenotypes of the phoY2::Tn mutant under hypoxia-induced dormancy. Taken together, our results indicate that PhoY2is required for maintaining metabolic homeostasis and adaption to environmental stress conditions (Part1).
The transition of latent to active TB is a complex process, which depends on the interaction between host and mycobacterium. In the second part of this work, we investigate the regulated role of microRNA (miRNA) in this process. miRNAs are endogenous,22-nucleotide RNAs that play important regulatory roles in animals and plants by targeting mRNAs for cleavage or translational repression. There are currently1,000human miRNAs sequences listed in the miRNA registry which may target about60%of all mammalian genes [http://www.mirbase.org/], indicating that these small molecules play fundamental and global functions in human biology, including development, differentiation, apoptosis, metabolism, viral infection, and cancer. MiRNAs also modulate the innate and adaptive immune responses to pathogens by affecting mammalian immune cell differentiation and the development of diseases of immunological origin.The clinical application of miRNAs as diagnostic or prognostic biomarkers has already been demonstrated in various types of cancers. However, compared to their well-known role in cancer, the role of miRNAs in susceptibility and resistance to infectious disease, especially those of bacterial origin, is still poorly understood. We compared the miRNA expression profiles of PBMCs from patients with active TB, subjects with LTBI, and healthy controls in order to test the hypothesis that candidate miRNAs regulate the transition from LTBI to active TB. We used a miRNA microarray chip containing,960probes to identify the differently expressed miRNAs, and performed realtime quantitative polymerase chain reaction (qPCR) for confirmation. The putative regulatory network of miRNAs that were differentially expressed in the samples from active TB and LTBI individuals was constructed based on predicted target genes and previously published genome-wide transcriptional profiles. Our study provides a greater understanding of the role of miRNAsmediated regulated networks in the transition from latent to active TB (Part
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2.卫生部2011年1月及2010年度全国法定传染病疫情报告
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