犬新孢子虫“警报素”介导的宿主Th1型免疫应答的研究
摘要
犬新孢子虫(Neospora caninum )是一种细胞内专性寄生的原虫,主要引起牛的流产。宿主和病原之间的免疫学的相互作用,在宿主防御和病原逃逸中起关键作用,可以刺激机体产生强烈的Th1型免疫应答。已有研究证明犬新孢子虫感染常会刺激机体细胞产生IFN-γ和IL-12等炎症因子,从而诱导机体Th1型免疫应答,然而,犬新孢子虫引起机体免疫应答的机制尚不清楚。本研究通过犬新孢子虫虫体抗原及其衍生的一组“警报素”-高迁移率组蛋白1来初步探讨引起机体Th1型免疫应答的机制,本研究有助于理解寄生虫和宿主的相互关系,为探讨犬新孢子虫致病机制及疫苗研制提供新的线索。
犬新孢子虫促进Th1型免疫应答反应研究:犬新孢子虫可以刺激机体产生Th1型免疫应答,可以诱导小鼠脾细胞和树突状细胞产生IL-12和IFN-γ;还可以诱导小鼠的巨噬细胞产生一氧化氮,但与细菌的LPS并没有协同作用,这说明犬新孢子虫可能与LPS的受体TLR4作用很小。有趣的是,犬新孢子虫活虫以及冻死、热死、超声破碎处理的虫体都可以大大提高CpG激活TLR9的能力,但是虫体自身对TLR9的作用却非常小,说明犬新孢子虫滋养体中存在某种组分参与激活TLR9,从而介导机体Th1型免疫应答,为下一步研究打下基础。
犬新孢子虫“警报素”基因的鉴定及定位的研究:众所周知,能结合DNA的蛋白除了核内的组蛋白外,就数“警报素”高迁移率组蛋白1家族(HMGB1)。犬新孢子虫全基因组有7个高迁移率组蛋白1(NcHMGB1)开放阅读框,其中只有NcHMGB1a、NcHMGB1b和NcHMGB1c三个蛋白包含HMGB B-box功能区。通过氨基酸序列比对,找到3个与人源HMGB1 B-box同源性为45%-54%的NcHMGB1蛋白,三个蛋白自身的同源性为43%-52%,与其他寄生性原虫如:疟原虫、巴贝斯虫、弓形虫同源性大约为48-50%、40-47%、43-96%,且都具有“TNF-a信号多肽区”。通过PCR扩增、原核表达,得到高纯度的重组蛋白,经鉴定这三个蛋白存在于虫体的可溶性组分中,并且只有NcHMGB1a是可分泌蛋白。因此,NcHMGB1是既可以存在细胞内又可以释放到细胞外的蛋白。对NcHMGB1蛋白的鉴定及纯化为下一步研究其功能提供了保障。
犬新孢子虫“警报素”体外致炎作用研究:NcHMGB1的重组蛋白为可溶性蛋白,它可以诱导小鼠的巨噬细胞产生TNF-α;三种NcHMGB1蛋白都可以刺激小鼠的树突状细胞产生IL-12,证明NcHMGB1的“TNF-α信号多肽区”具有跟哺乳动物细胞相同的功能,都可以刺激致炎细胞因子的生成,NcHMGB1是犬新孢子虫引起机体Th1型免疫应答的重要成员之一。
犬新孢子虫“警报素”介导Th1型免疫应答反应研究:NcHMGB1由于富含赖氨酸,可以绑定DNA。本试验证明NcHMGB1绑定DNA的比率为1.7±0.2,绑定的DNA分子量约为200-350bp,DNA测序表明,这些DNA覆盖整个E. coli基因组。含有细菌DNA的NcHMGB1不能协同CpG激活TLR9,但是经过DNase处理了的NcHMGB1蛋白可以协同CpG激活TLR9,其中蛋白和CpG的最佳浓度分别为1μg/mL和0.5μg/mL。抗NcHMGB1的抗体具有阻止其协同CpG的作用。在体外和体内NcHMGB1可以刺激机体产生IL-6、IL-12和CCL2等细胞炎症因子。因此,NcHMGB1参与了激活TLR9而介导机体Th1型免疫应答,进一步证明NcHMGB1是犬新孢子虫引起机体Th1型免疫应答的重要成员之一。
本研究证明犬新孢子虫介导的宿主先天性免疫应答的途径之一是通过激活TLR9途径。研究表明NcHMGB1是参与此免疫应答的PAMP重要成员之一。这表示NcHMGB1作为一种“警报素”,可以自由穿梭于细胞内外,在犬新孢子虫自身感染或与其他非特异性感染如细菌感染过程中,NcHMGB1可以绑定具有免疫原性的的DNA如CpG,从而大大激活CpG的受体TLR9,引起机体Th1型免疫反应,导致炎症的产生。对“警报素”的进一步的研究将有助于深入的了解宿主与寄生虫的相互关系,为防预与感染相关的免疫病理性疾病奠定了分子免疫学基础。
The intracellular parasite Neospora caninum has been known as a major cause of reproductive failure in cattle. It is indispensable that the host system is biased in favor of a type 1 immune response prior to initiation and generation of an effective acquired immunity. It has been documented that N. caninum (Nc) elicits a strong type 1 immune response, however, the mechanisms by which this parasite induces type 1 immune responses and associated immunopathology remain to be elucidated. The studies presented in this dissertation characterized the underlying mechanisms fostering a Th1 immune response by a group of Nc-derived "alarmins”, the high-mobility group box-1 (HMGB1) proteins.
Upregulation of type 1 immune responses and activation of TLR9 by N. caninum in the presence of CpG: Our studies showed that the Nc tachyzoites (NcTz) induced production of nitric oxide (NO) by macrophages and there was no synergistic effect between the parasite and bacterial lipopolysaccharide (LPS). Interestingly, live or killed NcTz or Nc lysate drastically enhanced the ability of CpG to activate the Toll-like receptor 9 (TLR9), although by themselves had little effect. This suggest that there is some compentent in NcTz to activation of TLR9 and induce type 1 immune responses.
Identification, cloning, expression, purification and localization of N. caninum high mobility group box 1 proteins : An Nc genome-wide search revealed 7 genes encoding proteins containing the HMGB motif, 3 of which, designated NcHMGB1a, NcHMGB1b and NcHMGB1c, code for the HMGB1 box B with moderate sequence homology among themselves. Cloning, expression, immunoblotting, and immunohistochemistry confirmed the presence of these proteins in the parasite with an apparent molecular mass of 5 to 18KDa. Only NcHMGB1a appeared to be secreted. So NcHMGB1 can present in intracellular and extraceller.
Upregulation of inflammatory cytokines by recombinant N. caninum HMGB1: Recombinant NcHMGB1 (rNcHMGB1) induced production of tumor-necrosis factor alpha (TNF-alpha) in a dose-dependent manner and all 3 isoforms stimulated interleukine-12 (IL-12) by dendritic cells. This suggest NcHMGB1 can induce type 1 immune responses.
Characterization of N.caninum HMGB1s as parasitic alarmins responsible for CpG- associated activation of TLR9 and regulation of inflammatory cytokine production: Due to their high content in lysine, NcHMGB1 bound to DNA efficiently at 1.7±0.2μg/μg recombinant protein, which was shown by the Hoechst DNA assay and gel shift assay. Next generation DNA sequencing of the bacterial DNA fragment isolated from rNcHMGB1 showed that NcHMGB1 bound to the entire E. coli genome. rNcHMGB1 alone or rNcHMGB1 plus CpG did not activate TLR9. However, DNase treatment to remove bacterial DNA fragment from rNcHMGB1 prior to addition of nuclease resistant CpG significantly augmented activation of TLR9. All 3 isofoms of NcHMGB1 were similarly potent in enhancing CpG activity with an optimal dose ratio of 1μg NcHMGB1 to 0.5μg CpG. Anti-rNcHMGB1 sera partially blocked the ability of NcHMGB1 to assist CpG in activating TLR9. rNcHMGB1+CpG also stimulated high level production of IL-6 by dendritic cells in a dose-dependent fashion. In vivo, rNcHMGB1a plus CpG stimulated high levels of IL-6 production 2h post injection and CCL2 6h post injection. The result showed that NcHMGB1 is the important compentent in NcTz to activation of TLR9 and induce type 1 immune responses.
These studies demonstrated that NcHMGB1 in part mediates activation of host innate immune responses by N. caninum through activation of TLR9. The results suggest that the unbound ("empty") NcHMGB1 may act as an¨alarmin〃during infection by itself or by non-specifically binding to immunogenic DNA such as CpG, activating host TLR9 and promoting an overall type 1 immunity. Further studies of this class of alarmins may facilitate in-depth understanding of the host-parasite interaction and aid in development of counter-measures for the control of infection-associated immunopathology.
犬新孢子虫促进Th1型免疫应答反应研究:犬新孢子虫可以刺激机体产生Th1型免疫应答,可以诱导小鼠脾细胞和树突状细胞产生IL-12和IFN-γ;还可以诱导小鼠的巨噬细胞产生一氧化氮,但与细菌的LPS并没有协同作用,这说明犬新孢子虫可能与LPS的受体TLR4作用很小。有趣的是,犬新孢子虫活虫以及冻死、热死、超声破碎处理的虫体都可以大大提高CpG激活TLR9的能力,但是虫体自身对TLR9的作用却非常小,说明犬新孢子虫滋养体中存在某种组分参与激活TLR9,从而介导机体Th1型免疫应答,为下一步研究打下基础。
犬新孢子虫“警报素”基因的鉴定及定位的研究:众所周知,能结合DNA的蛋白除了核内的组蛋白外,就数“警报素”高迁移率组蛋白1家族(HMGB1)。犬新孢子虫全基因组有7个高迁移率组蛋白1(NcHMGB1)开放阅读框,其中只有NcHMGB1a、NcHMGB1b和NcHMGB1c三个蛋白包含HMGB B-box功能区。通过氨基酸序列比对,找到3个与人源HMGB1 B-box同源性为45%-54%的NcHMGB1蛋白,三个蛋白自身的同源性为43%-52%,与其他寄生性原虫如:疟原虫、巴贝斯虫、弓形虫同源性大约为48-50%、40-47%、43-96%,且都具有“TNF-a信号多肽区”。通过PCR扩增、原核表达,得到高纯度的重组蛋白,经鉴定这三个蛋白存在于虫体的可溶性组分中,并且只有NcHMGB1a是可分泌蛋白。因此,NcHMGB1是既可以存在细胞内又可以释放到细胞外的蛋白。对NcHMGB1蛋白的鉴定及纯化为下一步研究其功能提供了保障。
犬新孢子虫“警报素”体外致炎作用研究:NcHMGB1的重组蛋白为可溶性蛋白,它可以诱导小鼠的巨噬细胞产生TNF-α;三种NcHMGB1蛋白都可以刺激小鼠的树突状细胞产生IL-12,证明NcHMGB1的“TNF-α信号多肽区”具有跟哺乳动物细胞相同的功能,都可以刺激致炎细胞因子的生成,NcHMGB1是犬新孢子虫引起机体Th1型免疫应答的重要成员之一。
犬新孢子虫“警报素”介导Th1型免疫应答反应研究:NcHMGB1由于富含赖氨酸,可以绑定DNA。本试验证明NcHMGB1绑定DNA的比率为1.7±0.2,绑定的DNA分子量约为200-350bp,DNA测序表明,这些DNA覆盖整个E. coli基因组。含有细菌DNA的NcHMGB1不能协同CpG激活TLR9,但是经过DNase处理了的NcHMGB1蛋白可以协同CpG激活TLR9,其中蛋白和CpG的最佳浓度分别为1μg/mL和0.5μg/mL。抗NcHMGB1的抗体具有阻止其协同CpG的作用。在体外和体内NcHMGB1可以刺激机体产生IL-6、IL-12和CCL2等细胞炎症因子。因此,NcHMGB1参与了激活TLR9而介导机体Th1型免疫应答,进一步证明NcHMGB1是犬新孢子虫引起机体Th1型免疫应答的重要成员之一。
本研究证明犬新孢子虫介导的宿主先天性免疫应答的途径之一是通过激活TLR9途径。研究表明NcHMGB1是参与此免疫应答的PAMP重要成员之一。这表示NcHMGB1作为一种“警报素”,可以自由穿梭于细胞内外,在犬新孢子虫自身感染或与其他非特异性感染如细菌感染过程中,NcHMGB1可以绑定具有免疫原性的的DNA如CpG,从而大大激活CpG的受体TLR9,引起机体Th1型免疫反应,导致炎症的产生。对“警报素”的进一步的研究将有助于深入的了解宿主与寄生虫的相互关系,为防预与感染相关的免疫病理性疾病奠定了分子免疫学基础。
The intracellular parasite Neospora caninum has been known as a major cause of reproductive failure in cattle. It is indispensable that the host system is biased in favor of a type 1 immune response prior to initiation and generation of an effective acquired immunity. It has been documented that N. caninum (Nc) elicits a strong type 1 immune response, however, the mechanisms by which this parasite induces type 1 immune responses and associated immunopathology remain to be elucidated. The studies presented in this dissertation characterized the underlying mechanisms fostering a Th1 immune response by a group of Nc-derived "alarmins”, the high-mobility group box-1 (HMGB1) proteins.
Upregulation of type 1 immune responses and activation of TLR9 by N. caninum in the presence of CpG: Our studies showed that the Nc tachyzoites (NcTz) induced production of nitric oxide (NO) by macrophages and there was no synergistic effect between the parasite and bacterial lipopolysaccharide (LPS). Interestingly, live or killed NcTz or Nc lysate drastically enhanced the ability of CpG to activate the Toll-like receptor 9 (TLR9), although by themselves had little effect. This suggest that there is some compentent in NcTz to activation of TLR9 and induce type 1 immune responses.
Identification, cloning, expression, purification and localization of N. caninum high mobility group box 1 proteins : An Nc genome-wide search revealed 7 genes encoding proteins containing the HMGB motif, 3 of which, designated NcHMGB1a, NcHMGB1b and NcHMGB1c, code for the HMGB1 box B with moderate sequence homology among themselves. Cloning, expression, immunoblotting, and immunohistochemistry confirmed the presence of these proteins in the parasite with an apparent molecular mass of 5 to 18KDa. Only NcHMGB1a appeared to be secreted. So NcHMGB1 can present in intracellular and extraceller.
Upregulation of inflammatory cytokines by recombinant N. caninum HMGB1: Recombinant NcHMGB1 (rNcHMGB1) induced production of tumor-necrosis factor alpha (TNF-alpha) in a dose-dependent manner and all 3 isoforms stimulated interleukine-12 (IL-12) by dendritic cells. This suggest NcHMGB1 can induce type 1 immune responses.
Characterization of N.caninum HMGB1s as parasitic alarmins responsible for CpG- associated activation of TLR9 and regulation of inflammatory cytokine production: Due to their high content in lysine, NcHMGB1 bound to DNA efficiently at 1.7±0.2μg/μg recombinant protein, which was shown by the Hoechst DNA assay and gel shift assay. Next generation DNA sequencing of the bacterial DNA fragment isolated from rNcHMGB1 showed that NcHMGB1 bound to the entire E. coli genome. rNcHMGB1 alone or rNcHMGB1 plus CpG did not activate TLR9. However, DNase treatment to remove bacterial DNA fragment from rNcHMGB1 prior to addition of nuclease resistant CpG significantly augmented activation of TLR9. All 3 isofoms of NcHMGB1 were similarly potent in enhancing CpG activity with an optimal dose ratio of 1μg NcHMGB1 to 0.5μg CpG. Anti-rNcHMGB1 sera partially blocked the ability of NcHMGB1 to assist CpG in activating TLR9. rNcHMGB1+CpG also stimulated high level production of IL-6 by dendritic cells in a dose-dependent fashion. In vivo, rNcHMGB1a plus CpG stimulated high levels of IL-6 production 2h post injection and CCL2 6h post injection. The result showed that NcHMGB1 is the important compentent in NcTz to activation of TLR9 and induce type 1 immune responses.
These studies demonstrated that NcHMGB1 in part mediates activation of host innate immune responses by N. caninum through activation of TLR9. The results suggest that the unbound ("empty") NcHMGB1 may act as an¨alarmin〃during infection by itself or by non-specifically binding to immunogenic DNA such as CpG, activating host TLR9 and promoting an overall type 1 immunity. Further studies of this class of alarmins may facilitate in-depth understanding of the host-parasite interaction and aid in development of counter-measures for the control of infection-associated immunopathology.
引文
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