感染弓形虫宿主的转录组及标识性microRNAs的研究
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摘要
刚地弓形虫是一种专性细胞内寄生虫，能广泛引起人类和温血动物的不同病理效应。根据弓形虫感染小鼠的毒力的不同可以分为三个克隆世系，I型虫株如RH株，公认是感染小鼠的最强毒株，造成宿主的非典型性弓形虫眼病。II型虫株如ME49株，其半数致死量低于RH株，是主要感染人类的虫株，III型虫株很少出现在人类病例中，具体原因尚不清楚。有研究表明90%以上的全身性弓形虫病患者死于弓形虫脑病。国内外许多科研工作者建立动物模型，用于探索弓形虫脑病的发病机制。基因芯片可系统分析宿主和病原体相互作用及宿主的全部基因组改变情况。这种工具被广泛的应用于鉴别细菌和病毒基因组表达的改变。基因芯片也被应用于寄生虫的基因表达分析，如艾美耳球虫和恶性疟原虫等。在弓形虫感染的研究中，以往的实验都是在细胞水平上的分析，对宿主体内感染知之甚少。许多的研究指出寄生虫感染宿主神经细胞后能引起宿主行为的改变，但没有阐明原因。为更好的理解感染弓形虫后宿主与寄生虫之间的相互作用关系，我们开展了以下几个方面的研究。
在第一个研究中，我们系统地分析了感染弓形虫I型RH株和II型ME49株小鼠脑组织和淋巴细胞的转录组情况。分离感染弓形虫RH株，ME49株小鼠和健康小鼠脑组织及淋巴细胞总RNA，各组样本cRNA与荧光染料Cy3结合，被标记的cRNA与小鼠表达谱全基因芯片杂交。分析脑组织和淋巴细胞感染弓形虫后的基因组表达水平，并对差异基因通过Q-PCR进一步验证。利用GO、Pathway和Signal-Net分析数据，结果显示在不同毒力株弓形虫急性感染时，小鼠的神经和免疫系统应答反应具有明显的差异。弓形虫强毒株对小鼠神经系统的损伤作用强于弱毒株虫体，并且宿主的先天性免疫反应比较明显，获得性免疫反应受到抑制。感染弓形虫弱毒株后，脑组织和外周淋巴细胞的先天性免疫反应和获得性免疫反应均强于感染弓形虫强毒株的小鼠。不同刚地弓形虫株对宿主神经和免疫系统应答的调节都具有显著差异，这可能与虫株的特异性有关。积极开展对弓形虫脑病的研究和探索其发病机制是保护人类健康的重要工作。
另一方面，弓形虫病在亚洲，非洲，南美洲包括欧洲均有报道。弓形虫病的及时诊断可降低由弓形虫引起的宿主相关损伤。弓形虫病在免疫抑制的患者和孕妇体内造成严重后果，新生儿将导致听力、视力、神经系统疾病，对孕妇的早期治疗可避免新生儿感染。因此，我们迫切需要寻找一种更为敏感和特异的弓形虫病诊断方法。microRNAs（miRNAs）是由21-25个核苷酸组成的非编码小RNA分子，可能在宿主生理和病理过程中发挥重要作用。miRNAs可稳定存在血浆中，已被证实血浆miRNAs作为生物诊断标识物应用于人类癌症检测。到目前为止，还没有关于感染弓形虫的宿主血浆中用于诊断的循环miRNAs的报道。
在第二个研究中，通过Q-PCR array筛选了在小鼠体内具有重要功能的414个miRNAs，其中mmu-miR-712-3p，mmu-miR-511-5p和mmu-miR-217-5p三个miRNAs显著性上调，进一步在感染弓形虫的小鼠、大鼠和人类的血浆样本中验证了这三个miRNAs的表达水平，结果发现这三个miRNAs与弓形虫感染具有显著相关性。血浆循环miRNAs：miR-712-3p，miR-511-5p和miR-217-5p有希望成为弓形虫病诊断新型标识物，这一结果为进一步预测临床弓形虫病打下基础，为临床医生能够快速准确的掌握患者病情提供帮助。
Toxoplasma gondii （T. gondii） is an obligatory intracellular parasite thatcauses diverse pathological effects in humans and other warm-blooded vertebrates. T.gondii has an unusual clonal population structure which exists with limited geneticdiversity but belongs to three distinct clonal lineages and displays markedly differentlevels of virulence in mice. Type I strain, such as RH strain, is considered as themost virulent strain in mice, and it has been frequently found in individuals at risk ofatypical ocular toxoplasmosis. Type II strain, like ME49strain is less pathogenicwith lower LD50value than that of RH strain and this strain has been found in themajority of human infection. Type III strain is rarely found in humans, but thereason is unclear. The investigation showed that more than90%of the patientssuffered from systemic toxoplasmosis died of toxoplasmic encephalitis. Manyresearchers have established animal model to explore the pathogenesis oftoxoplasmic encephalitis. Microarray represents the first generation of analyticaltools with the capacity of global gene expression profiling in both pathogendevelopment and host-pathogen interactions. It has been extensively used to identifyalterations in gene expression of bacterial and viral infection. Microarray has alsobeen used to investigate gene expression of parasites such as Eimeria maxima andPlasmodium falciparum. However, all these studies were performed with cell linesinfected by T. gondii, whereas little is known about changes in hosts in vivo.Furthermore, several studies have indicated that parasite infection in the host neuralcells may cause behavioral alterations, but no conclusive evidence has beenidentified. More studies are still necessary in order to increase our understanding ofhost–parasite interactions in T. gondii infection.
In this study, we systematically analyzed the transcriptomes in both brain tissues and peripheral lymphocytes in BALB/c mice infected with Type I (RH strain)and II (ME49strain) T. gondii respectively. Total RNA of brain tissues andperipheral lymphocytes of BALB/c mice infected with RH and ME49strain T.gondii as well as that of healthy mice were purified and converted to cRNA withincorporated Cy3. The labeled cRNA probes were hybridized to the Whole MouseGenome Microarray. The impact of parasite infection on gene expression in bothbrain tissues and peripheral lymphocytes were analyzed. Differentially expressedgenes were revalidated with real-time quantitative reverse transcriptase-polymerasechain reaction (Q-PCR). Data indicated that the genes associated with immunitywere up-regulated after infection by the two parasite strains, but significantup-regulation was observed in both brain tissues and peripheral lymphocytes of miceinfected with ME49strain compared to that infected by RH strain. The pathwaysrelated to pathogenesis of the nervous system were more significantly up-regulatedin mice infected with RH strain. Genetically distinct T. gondii strains showed cleardifferences in modulation of host pathophysiological and immunological responsesin both brain tissues and peripheral lymphocytes. It was likely that some of the hostresponses to T. gondii infection were universal, but the immune response and CNSreaction were in a strain-specific manner.
Toxoplasmosis caused by T. gondii is a worldwide intracellular parasitic diseasethat varies from Asian, Africa, South America to Europe. Detection of early-stagetoxoplasmosis is a key measure to reduce toxoplasmosis-related health damage. Theparasite can cause severe disease in immunocompromised patients and mothersduring pregnancy. Toxoplasmosis may cause serious consequences for a new bornbaby, such as hearing and sight impairment, neurological symptoms. Early treatmentof pregnant women could reduce the incidence of sequelae in infected infants.Therefore, an ideal method with high specificity and sensitivity for diagnosis oftoxoplasmosis has been asked for urgently. microRNAs (miRNAs) are21-25nucleotides noncoding RNA molecules that could play important roles in physiological and pathologic processes. Recently, it has been reported that miRNAsare stably detectable in plasma. It has been confirmed that plasma miRNAs werediagnosis biomarkers for human cancer. But to our knowledge, there is no report onthe role of circulating miRNAs in the plasma of host infected with T. gondii.
In this study, real-time PCR array was applied to measure414miRNAs fromplasma of mice infected by T. gondii. We focused on mmu-miR-712-3p,mmu-miR-511-5p and mmu-miR-217-5p, which were detected abundantly in miceinfected with T. gondii. Quantitative analysis of these miRNAs in a large set plasmaof mice, rats and human showed that mmu-miR-712-3p, mmu-miR-511-5p andmmu-miR-217-5p were potentially useful for diagnosis with a satisfactory degree ofsensitivity and specificity. In conclusion, plasma miR-712-3p, miR-511-5p andmiR-217-5p appear to be novel biomarkers for detection of toxoplasmosis. Our datamay serve as basis for further research to predict the clinical toxoplasmosis.
在第一个研究中，我们系统地分析了感染弓形虫I型RH株和II型ME49株小鼠脑组织和淋巴细胞的转录组情况。分离感染弓形虫RH株，ME49株小鼠和健康小鼠脑组织及淋巴细胞总RNA，各组样本cRNA与荧光染料Cy3结合，被标记的cRNA与小鼠表达谱全基因芯片杂交。分析脑组织和淋巴细胞感染弓形虫后的基因组表达水平，并对差异基因通过Q-PCR进一步验证。利用GO、Pathway和Signal-Net分析数据，结果显示在不同毒力株弓形虫急性感染时，小鼠的神经和免疫系统应答反应具有明显的差异。弓形虫强毒株对小鼠神经系统的损伤作用强于弱毒株虫体，并且宿主的先天性免疫反应比较明显，获得性免疫反应受到抑制。感染弓形虫弱毒株后，脑组织和外周淋巴细胞的先天性免疫反应和获得性免疫反应均强于感染弓形虫强毒株的小鼠。不同刚地弓形虫株对宿主神经和免疫系统应答的调节都具有显著差异，这可能与虫株的特异性有关。积极开展对弓形虫脑病的研究和探索其发病机制是保护人类健康的重要工作。
另一方面，弓形虫病在亚洲，非洲，南美洲包括欧洲均有报道。弓形虫病的及时诊断可降低由弓形虫引起的宿主相关损伤。弓形虫病在免疫抑制的患者和孕妇体内造成严重后果，新生儿将导致听力、视力、神经系统疾病，对孕妇的早期治疗可避免新生儿感染。因此，我们迫切需要寻找一种更为敏感和特异的弓形虫病诊断方法。microRNAs（miRNAs）是由21-25个核苷酸组成的非编码小RNA分子，可能在宿主生理和病理过程中发挥重要作用。miRNAs可稳定存在血浆中，已被证实血浆miRNAs作为生物诊断标识物应用于人类癌症检测。到目前为止，还没有关于感染弓形虫的宿主血浆中用于诊断的循环miRNAs的报道。
在第二个研究中，通过Q-PCR array筛选了在小鼠体内具有重要功能的414个miRNAs，其中mmu-miR-712-3p，mmu-miR-511-5p和mmu-miR-217-5p三个miRNAs显著性上调，进一步在感染弓形虫的小鼠、大鼠和人类的血浆样本中验证了这三个miRNAs的表达水平，结果发现这三个miRNAs与弓形虫感染具有显著相关性。血浆循环miRNAs：miR-712-3p，miR-511-5p和miR-217-5p有希望成为弓形虫病诊断新型标识物，这一结果为进一步预测临床弓形虫病打下基础，为临床医生能够快速准确的掌握患者病情提供帮助。
Toxoplasma gondii （T. gondii） is an obligatory intracellular parasite thatcauses diverse pathological effects in humans and other warm-blooded vertebrates. T.gondii has an unusual clonal population structure which exists with limited geneticdiversity but belongs to three distinct clonal lineages and displays markedly differentlevels of virulence in mice. Type I strain, such as RH strain, is considered as themost virulent strain in mice, and it has been frequently found in individuals at risk ofatypical ocular toxoplasmosis. Type II strain, like ME49strain is less pathogenicwith lower LD50value than that of RH strain and this strain has been found in themajority of human infection. Type III strain is rarely found in humans, but thereason is unclear. The investigation showed that more than90%of the patientssuffered from systemic toxoplasmosis died of toxoplasmic encephalitis. Manyresearchers have established animal model to explore the pathogenesis oftoxoplasmic encephalitis. Microarray represents the first generation of analyticaltools with the capacity of global gene expression profiling in both pathogendevelopment and host-pathogen interactions. It has been extensively used to identifyalterations in gene expression of bacterial and viral infection. Microarray has alsobeen used to investigate gene expression of parasites such as Eimeria maxima andPlasmodium falciparum. However, all these studies were performed with cell linesinfected by T. gondii, whereas little is known about changes in hosts in vivo.Furthermore, several studies have indicated that parasite infection in the host neuralcells may cause behavioral alterations, but no conclusive evidence has beenidentified. More studies are still necessary in order to increase our understanding ofhost–parasite interactions in T. gondii infection.
In this study, we systematically analyzed the transcriptomes in both brain tissues and peripheral lymphocytes in BALB/c mice infected with Type I (RH strain)and II (ME49strain) T. gondii respectively. Total RNA of brain tissues andperipheral lymphocytes of BALB/c mice infected with RH and ME49strain T.gondii as well as that of healthy mice were purified and converted to cRNA withincorporated Cy3. The labeled cRNA probes were hybridized to the Whole MouseGenome Microarray. The impact of parasite infection on gene expression in bothbrain tissues and peripheral lymphocytes were analyzed. Differentially expressedgenes were revalidated with real-time quantitative reverse transcriptase-polymerasechain reaction (Q-PCR). Data indicated that the genes associated with immunitywere up-regulated after infection by the two parasite strains, but significantup-regulation was observed in both brain tissues and peripheral lymphocytes of miceinfected with ME49strain compared to that infected by RH strain. The pathwaysrelated to pathogenesis of the nervous system were more significantly up-regulatedin mice infected with RH strain. Genetically distinct T. gondii strains showed cleardifferences in modulation of host pathophysiological and immunological responsesin both brain tissues and peripheral lymphocytes. It was likely that some of the hostresponses to T. gondii infection were universal, but the immune response and CNSreaction were in a strain-specific manner.
Toxoplasmosis caused by T. gondii is a worldwide intracellular parasitic diseasethat varies from Asian, Africa, South America to Europe. Detection of early-stagetoxoplasmosis is a key measure to reduce toxoplasmosis-related health damage. Theparasite can cause severe disease in immunocompromised patients and mothersduring pregnancy. Toxoplasmosis may cause serious consequences for a new bornbaby, such as hearing and sight impairment, neurological symptoms. Early treatmentof pregnant women could reduce the incidence of sequelae in infected infants.Therefore, an ideal method with high specificity and sensitivity for diagnosis oftoxoplasmosis has been asked for urgently. microRNAs (miRNAs) are21-25nucleotides noncoding RNA molecules that could play important roles in physiological and pathologic processes. Recently, it has been reported that miRNAsare stably detectable in plasma. It has been confirmed that plasma miRNAs werediagnosis biomarkers for human cancer. But to our knowledge, there is no report onthe role of circulating miRNAs in the plasma of host infected with T. gondii.
In this study, real-time PCR array was applied to measure414miRNAs fromplasma of mice infected by T. gondii. We focused on mmu-miR-712-3p,mmu-miR-511-5p and mmu-miR-217-5p, which were detected abundantly in miceinfected with T. gondii. Quantitative analysis of these miRNAs in a large set plasmaof mice, rats and human showed that mmu-miR-712-3p, mmu-miR-511-5p andmmu-miR-217-5p were potentially useful for diagnosis with a satisfactory degree ofsensitivity and specificity. In conclusion, plasma miR-712-3p, miR-511-5p andmiR-217-5p appear to be novel biomarkers for detection of toxoplasmosis. Our datamay serve as basis for further research to predict the clinical toxoplasmosis.
引文
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