结核分枝杆菌广谱胁迫蛋白Rv2624c的功能研究
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摘要
结核分枝杆菌(Mycobacterium tuberculosis,Mtb)是导致结核病的病原菌。全球约有三分之一的人口感染结核分枝杆菌,每年约有两百万人死于结核病,因此结核病成为严重威胁人类健康的疾病之一。据估计,人类感染结核分枝杆菌后,只有10%的感染能够转化为活动性肺结核；在其余90%的感染中,细菌在宿主肺部存留维持代谢休眠状态而进入潜伏感染期。结核分枝杆菌的潜伏感染在结核病发病机理中起非常重要的作用,但是目前相关的调节机制尚不明确。近年来已有研究证明结核分枝杆菌的广谱胁迫蛋白(Universal Stress Protein,USP)家族与潜伏感染有关,研究这类家族蛋白的功能,以期为结核分枝杆菌的潜伏感染研究提供一些线索。
广谱胁迫蛋白是一种古老且保守的蛋白家族,当细菌处于环境压力胁迫情况下,比如营养物质缺乏,缺氧,NO胁迫,生长环境中有重金属离子等毒性物质存在,热休克以及DNA损伤等,该家族蛋白参与表达调控,有助于维持细菌在压力下存活。感染宿主的结核分枝杆菌被巨噬细胞吞噬后逐步形成肉芽肿,此时的结核分枝杆菌恰好就处于氧气、营养物质缺乏的压力环境中。结核分枝杆菌包含十个广谱胁迫蛋白,研究表明其中一个广谱胁迫蛋白Rv2623是细菌进入慢性感染期必须的蛋白,该蛋白能够调节结核分枝杆菌在体内和体外的生长,并且这种调节与蛋白结合ATP的功能有关,提示该家族蛋白与结核分枝杆菌的潜伏感染形成具有密切关系。
本论文主要针对结核分枝杆菌广谱胁迫蛋白Rv2624c进行功能研究。首先构建Rv2624c在大肠杆菌(E.coli中的重组表达质粒,将该蛋白在大肠杆菌中进行表达纯化,并且用纯蛋白免疫新西兰大白兔制作抗Rv2624c的兔多克隆抗体。通过对Rv2624c纯蛋白进行生化活性检测,证实了Rv2624c具有ATP结合能力但体外单独存在时不具有ATP酶活性。对该蛋白ATP结合保守区域的氨基酸进行点突变后,突变体的ATP结合能力下降,证明了突变的氨基酸在蛋白对ATP的结合中起关键性作用。其次对过表达Rv2624c野生型和突变体的耻垢分枝杆菌进行了绘制生长曲线实验和斑点生长实验,结果显示过表达Rv2624c对耻垢分枝杆菌的体外生长没有影响。同时,用过表达Rv2624c野生型和突变体的耻垢分枝杆菌侵染巨噬细胞THP1后比较细菌存活率,我们发现Rv2624c过表达的耻垢分枝杆菌的存活率高于对照菌株,且突变体的存活率趋势与ATP结合能力大小成正比。
转录组测序分析表明,对差异表达的基因进行KEGG pathway显著性富集分析,我们发现过表达Rv2624c的耻垢分枝杆菌和对照菌株相比差异最大的通路是精氨酸脯氨酸代谢通路以及色氨酸代谢通路。通过荧光实时定量PCR验证Rv2624c过表达的耻垢分枝杆菌中这两条通路的相关基因在转录组水平上与对照菌株相比表达量增高。有报道显示精氨酸是与结核分枝杆菌在压力环境中生长有关的氨基酸,而色氨酸的合成能够抑制CD4T细胞介导的对结核分枝杆菌的杀伤作用。因此,我们推测Rv2624c的功能与精氨酸和色氨酸代谢通路有关。我们通过BlastX比对找出这两条代谢通路的基因在牛分枝杆菌(M.bovis,BCG)中的同功能基因,对过表达Rv2624c的牛分枝杆菌进行荧光定量PCR验证这些同功能基因的表达量也有增高,提示Rv2624c的功能与精氨酸脯氨酸代谢通路和色氨酸代谢通路有关。
综上所述,本研究证明了Rv2624c具有ATP结合活性,对Rv2624c ATP结合保守区域的氨基酸进行突变后蛋白的ATP结合能力下降。Rv2624c及突变体在耻垢分枝杆菌中的过表达均对耻垢分枝杆菌的体外生长没有影响,而过表达Rv2624c的耻垢分枝杆菌在侵染巨噬细胞THP1后存活率增高。在转录组水平上发现导致这种表型的差异基因富集通路是精氨酸脯氨酸代谢通路和色氨酸代谢通路,并通过荧光实时定量PCR证实了该通路中相关基因表达量增高。在过表达Rv2624c的BCG中找到了这些基因的同功能基因,经验证表达量也增高,提示Rv2624c的功能可能与精氨酸脯氨酸代谢通路和色氨酸代谢通路有关,为结核分枝杆菌USP的研究提供了线索。
Mycobacterium tuberculosis (Mtb) is a pathogenic bacteria species in the genus Mycobacterium and the causative agent of most cases of tuberculosis (TB). TB is the second leading cause of death in the world from a bacterial infectious disease. The World Health Organizaiton (WHO) estimates that approximately one-third of the world's population is infected with Mtb and2million individuals die of TB. Only about10%of tuberculosis infections lead to active pulmonary disease. In the remaining90%of tuberculosis cases, initial infection is contained by the host's immune system and active disease dose not develop. This situation is called Latent TB Infection (LTBI). The stable LTBI state is achieved by the ability of Mtb to attenuate and evade host mycobactericidal responses. Inadequate immunity leads to mycobacterial multiplication and clinical disease. It's dangerous when dormant Mtb turn reactivation. Unfortunately, the mechanisms that regulate these processes remain unclear. Recent researches show that Universal Stress Protein(USP) superfamily is associated with the latency. We study functions of these proteins in order to provide valuable insight into tuberculosis dormancy and uncover new chances for the development of antituberculosis therapies.
The USP superfamily is an acient and well-conserved protein family represented in diverse organisms from Archae and Eubacteria to yeast, fungi and plants. USP can be reduced in response to a wide variety of growth-arrested conditions, for examples, heat shock, DNA damage, NO, exhaustion of any one of number of nutrients, presence of a variety of toxic agents including heavy metals, hypoxia. Researchs about Rv2623which is one of the Mtb USP, suggest that i) Rv2623regulates growth of Mtb in vivo and vitro, ii)Rv2623is required for the Mtb entry into the chronic phase of infection in the host, iii)Rv2623binds ATP, iv)the growth-regulatory is related to its ATP-binding activity. The results indicate that USP and Mtb dormancy are relevant.
Our studies show that Rv2624c which is another USP of Mtb binds ATP while it isn't an ATPase when it is alone in vitro. We engineered mutations within D17E and G109A conserved amio acids to disrupt ATP binding. ATP quantificaition analysis of nucleotides bound from E.coli-purified Rv2624cD17E,Rv2624cG109and Rv2624cD17EG109revealed that the mutant proteins are deficient in ATP-binding. The wild type and D17E, G109A, D17EG109A mutant proteins were overexpressed in M.smegmatis and tested by anti-Rv2624c rabbit polyclonal antibody. The D17E and D17EG109A overexpressed at different levels compared to wile type Rv2624c. We examined the effect of overexpression of Rv2624c and mutants on the rapidly growing M.smegmatis MC2155. The results showed that the growth kinetics of mutants are comparable to that of wildtype. We also determined M.smegmatis which overexpressed Rv2624c exhibited a increase survival in macrophages THP1. We utilized RNA-seq to explore the transcriptome of M.smegmatis which overexpressed Rv2624c in order to explain above phenotype. Two profiles of M.smegmatis which overexpressed Rv2624c and control were generated after a physical ribosome RNA removal step. We systematically described the transcriptome and analyzed the functions for the differentiated expressed genes between the two strains, and finally chose arginine/proline metabolism pathway and tryptophan metabolism pathway which predicted to be related to the survival in macrophages.10upregulated genes selected from two pathways were validated by RT-qPCR.7homologous genes of above10genes can be found in M.bovis and also were validated upregulated by RT-qPCR in M.bovis which overexpressed Rv2624c. So we predicted the fuction of Rv2624c is related to arginine/proline metabolism pathway and tryptophan metabolism pathway. Our studies indicate that Rv2624c is very impotant in survival in macrophage for mycobacterium and provide clues for USP studies.
广谱胁迫蛋白是一种古老且保守的蛋白家族,当细菌处于环境压力胁迫情况下,比如营养物质缺乏,缺氧,NO胁迫,生长环境中有重金属离子等毒性物质存在,热休克以及DNA损伤等,该家族蛋白参与表达调控,有助于维持细菌在压力下存活。感染宿主的结核分枝杆菌被巨噬细胞吞噬后逐步形成肉芽肿,此时的结核分枝杆菌恰好就处于氧气、营养物质缺乏的压力环境中。结核分枝杆菌包含十个广谱胁迫蛋白,研究表明其中一个广谱胁迫蛋白Rv2623是细菌进入慢性感染期必须的蛋白,该蛋白能够调节结核分枝杆菌在体内和体外的生长,并且这种调节与蛋白结合ATP的功能有关,提示该家族蛋白与结核分枝杆菌的潜伏感染形成具有密切关系。
本论文主要针对结核分枝杆菌广谱胁迫蛋白Rv2624c进行功能研究。首先构建Rv2624c在大肠杆菌(E.coli中的重组表达质粒,将该蛋白在大肠杆菌中进行表达纯化,并且用纯蛋白免疫新西兰大白兔制作抗Rv2624c的兔多克隆抗体。通过对Rv2624c纯蛋白进行生化活性检测,证实了Rv2624c具有ATP结合能力但体外单独存在时不具有ATP酶活性。对该蛋白ATP结合保守区域的氨基酸进行点突变后,突变体的ATP结合能力下降,证明了突变的氨基酸在蛋白对ATP的结合中起关键性作用。其次对过表达Rv2624c野生型和突变体的耻垢分枝杆菌进行了绘制生长曲线实验和斑点生长实验,结果显示过表达Rv2624c对耻垢分枝杆菌的体外生长没有影响。同时,用过表达Rv2624c野生型和突变体的耻垢分枝杆菌侵染巨噬细胞THP1后比较细菌存活率,我们发现Rv2624c过表达的耻垢分枝杆菌的存活率高于对照菌株,且突变体的存活率趋势与ATP结合能力大小成正比。
转录组测序分析表明,对差异表达的基因进行KEGG pathway显著性富集分析,我们发现过表达Rv2624c的耻垢分枝杆菌和对照菌株相比差异最大的通路是精氨酸脯氨酸代谢通路以及色氨酸代谢通路。通过荧光实时定量PCR验证Rv2624c过表达的耻垢分枝杆菌中这两条通路的相关基因在转录组水平上与对照菌株相比表达量增高。有报道显示精氨酸是与结核分枝杆菌在压力环境中生长有关的氨基酸,而色氨酸的合成能够抑制CD4T细胞介导的对结核分枝杆菌的杀伤作用。因此,我们推测Rv2624c的功能与精氨酸和色氨酸代谢通路有关。我们通过BlastX比对找出这两条代谢通路的基因在牛分枝杆菌(M.bovis,BCG)中的同功能基因,对过表达Rv2624c的牛分枝杆菌进行荧光定量PCR验证这些同功能基因的表达量也有增高,提示Rv2624c的功能与精氨酸脯氨酸代谢通路和色氨酸代谢通路有关。
综上所述,本研究证明了Rv2624c具有ATP结合活性,对Rv2624c ATP结合保守区域的氨基酸进行突变后蛋白的ATP结合能力下降。Rv2624c及突变体在耻垢分枝杆菌中的过表达均对耻垢分枝杆菌的体外生长没有影响,而过表达Rv2624c的耻垢分枝杆菌在侵染巨噬细胞THP1后存活率增高。在转录组水平上发现导致这种表型的差异基因富集通路是精氨酸脯氨酸代谢通路和色氨酸代谢通路,并通过荧光实时定量PCR证实了该通路中相关基因表达量增高。在过表达Rv2624c的BCG中找到了这些基因的同功能基因,经验证表达量也增高,提示Rv2624c的功能可能与精氨酸脯氨酸代谢通路和色氨酸代谢通路有关,为结核分枝杆菌USP的研究提供了线索。
Mycobacterium tuberculosis (Mtb) is a pathogenic bacteria species in the genus Mycobacterium and the causative agent of most cases of tuberculosis (TB). TB is the second leading cause of death in the world from a bacterial infectious disease. The World Health Organizaiton (WHO) estimates that approximately one-third of the world's population is infected with Mtb and2million individuals die of TB. Only about10%of tuberculosis infections lead to active pulmonary disease. In the remaining90%of tuberculosis cases, initial infection is contained by the host's immune system and active disease dose not develop. This situation is called Latent TB Infection (LTBI). The stable LTBI state is achieved by the ability of Mtb to attenuate and evade host mycobactericidal responses. Inadequate immunity leads to mycobacterial multiplication and clinical disease. It's dangerous when dormant Mtb turn reactivation. Unfortunately, the mechanisms that regulate these processes remain unclear. Recent researches show that Universal Stress Protein(USP) superfamily is associated with the latency. We study functions of these proteins in order to provide valuable insight into tuberculosis dormancy and uncover new chances for the development of antituberculosis therapies.
The USP superfamily is an acient and well-conserved protein family represented in diverse organisms from Archae and Eubacteria to yeast, fungi and plants. USP can be reduced in response to a wide variety of growth-arrested conditions, for examples, heat shock, DNA damage, NO, exhaustion of any one of number of nutrients, presence of a variety of toxic agents including heavy metals, hypoxia. Researchs about Rv2623which is one of the Mtb USP, suggest that i) Rv2623regulates growth of Mtb in vivo and vitro, ii)Rv2623is required for the Mtb entry into the chronic phase of infection in the host, iii)Rv2623binds ATP, iv)the growth-regulatory is related to its ATP-binding activity. The results indicate that USP and Mtb dormancy are relevant.
Our studies show that Rv2624c which is another USP of Mtb binds ATP while it isn't an ATPase when it is alone in vitro. We engineered mutations within D17E and G109A conserved amio acids to disrupt ATP binding. ATP quantificaition analysis of nucleotides bound from E.coli-purified Rv2624cD17E,Rv2624cG109and Rv2624cD17EG109revealed that the mutant proteins are deficient in ATP-binding. The wild type and D17E, G109A, D17EG109A mutant proteins were overexpressed in M.smegmatis and tested by anti-Rv2624c rabbit polyclonal antibody. The D17E and D17EG109A overexpressed at different levels compared to wile type Rv2624c. We examined the effect of overexpression of Rv2624c and mutants on the rapidly growing M.smegmatis MC2155. The results showed that the growth kinetics of mutants are comparable to that of wildtype. We also determined M.smegmatis which overexpressed Rv2624c exhibited a increase survival in macrophages THP1. We utilized RNA-seq to explore the transcriptome of M.smegmatis which overexpressed Rv2624c in order to explain above phenotype. Two profiles of M.smegmatis which overexpressed Rv2624c and control were generated after a physical ribosome RNA removal step. We systematically described the transcriptome and analyzed the functions for the differentiated expressed genes between the two strains, and finally chose arginine/proline metabolism pathway and tryptophan metabolism pathway which predicted to be related to the survival in macrophages.10upregulated genes selected from two pathways were validated by RT-qPCR.7homologous genes of above10genes can be found in M.bovis and also were validated upregulated by RT-qPCR in M.bovis which overexpressed Rv2624c. So we predicted the fuction of Rv2624c is related to arginine/proline metabolism pathway and tryptophan metabolism pathway. Our studies indicate that Rv2624c is very impotant in survival in macrophage for mycobacterium and provide clues for USP studies.
引文
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