建立HHV-6体外感染U251细胞模型并对其生物学功能及机制的研究
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摘要
人类疱疹病毒6型(Human herpesvirus 6,HHV-6)是一类嗜人淋巴细胞的双链DNA病毒,于1986年由美国癌症中心的Salahuddin等首先从淋巴增生性疾病患者外周血单个核细胞中分离到,对其进行抗原性和酶切图谱分析表明,它有别于其它疱疹病毒,是一种具有疱疹病毒科形态特征和嗜淋巴细胞特性的新型疱疹病毒,故命名为人类疱疹病毒6型,属于疱疹病毒β亚科。HHV-6可分为A和B两个亚型。HHV-6感染具有广泛的嗜细胞性,主要侵犯CD4+T细胞、单核巨噬细胞及神经胶质细胞等。1988年日本学者Yamanishi确认了HHV-6是婴幼儿急疹(ES)的病原体,后来有报道神经胶质瘤、脑炎、慢性疲劳综合症、器官移植后感染、多发性硬化症等多种疾病有关,但对其致病机制尚不清楚。
神经胶质瘤(Glioma)是人类最常见的原发性脑肿瘤,到目前为止对其病因不清楚。近年来病毒在神经胶质瘤发生发展中的作用引起了多学科的广泛关注。有多篇报道在神经胶质瘤患者瘤组织中能检测到HHV-6 DNA的存在,但未能拿到病毒。人神经胶质瘤U251细胞是一种星形胶质瘤细胞株,具有星形胶质细胞部分特性,因此若能够建立HHV-6体外感染U251细胞模型,对研究HHV-6与神经胶质瘤的关系有指导意义。
本论文分三个部分,(一)HHV-6GS株在CBMCs中的培养扩增及病毒效价的滴定。通过PCR检测到HHV-6的DNA,间接免疫荧光检测到HHV-6抗原。病毒的滴度最终确定约为5×103TCID50/ml。(二)HHV-6感染神经胶质瘤U251细胞建立体外感染模型。结果发现HHV-6能感染U251细胞引起细胞病变,促进细胞增殖,使细胞周期发生改变及细胞因子IL-6分泌增加;成功建立了体外感染的模型。(三)对有丝分裂原活化蛋白激酶(mitogen-activated protein kinase , MAPK)信号通路的分支JNK和P38通路进行研究。结果发现在HHV-6的作用下磷酸化JNK和P38蛋白表达增加,病毒感染可能通过活化JNK和P38信号通路,引起肿瘤细胞的分化。
在成功建立HHV-6感染U251细胞体外模型的基础上,对HHV-6感染神经胶质瘤U251细胞的功能及机制作了初步研究,结果说明HHV-6与神经胶质瘤的发生发展存在一定的联系,为进一步研究神经胶质瘤的病毒病因和发病机理提供理论和实验依据。
Human herpes virus-6 (Human herpesvirus 6, HHV-6) is a kind of double-stranded DNA in human lymphocytes addicted virus. In 1986, Salahuddin et al were the first to isolate HHV-6 using peripheral blood mononuclear cells obtained from patients with lymphoid hyperplasia in the American Cancer Center. Two genetically distinct variants of the virus exist, HHV-6A and -6B. HHV-6 is aβ-herpesvirus related to HHV-7 and, to a lesser extent, human cytomegalovirus (HCMV). HHV-6 infection has a broad tropism, the main violations of CD4 + T cells, monocytes macrophages and glial cells. In 1988, Yamanishi et al confirmed HHV-6 is the pathogen of acute measles in infants and children (ES). Later, HHV-6 has been linked with many other kinds of diseases, including glioma, encephalitis, chronic fatigue syndrome, post-transplant infections and multiple sclerosis,although the significance of the associations is unclear.
Glioma is the most common primary brain malignant tumor. To date, the etiology is unclear.Recently, the role of virus in the development and progression of gliomas has caused widespread concern. A number of articles have reported that HHV-6 DNA can be detected by PCR in glioma tissue , but failed to get the virus. Human glioma U251 cell is a glioma cell line with some characteristics of astrocytes. So if it can be infected with HHV-6 in vitro, the study of relationship between HHV-6 and glioma can be carried.
The thesis contains three parts, (i) HHV-6 GS was inoculated in CBMCs, HHV-6 DNA and antigen were detected by PCR and IF respectively. Virus titer was determined as 5×103TCID50/ml. (ii) U251 cells can be infected with HHV-6 in vitro, resulting in CPE, cell proliferation, alteration of cell cycle and increasing the secretion of IL-6. (iii) The study of JNK and P38 pathway related todvision and differentiation of tumor cells. The results showed that HHV-6 increased the expression of the phosphorylated JNK and P38 proteins in U251 cells. Maybe the virus can induce the differentiation of tumor cells through activating JNK and P38 pathway.
The establishment of U251 cells infected with HHV-6 in vitro and the preliminary study of HHV-6 affecting the biological function of U251 cells and its mechanism illustrated that HHV-6 was linked to the occurrence and development of glioma,.It provides the theoretical and experimental basis to further study the etiology and pathogenesis of glioma.
神经胶质瘤(Glioma)是人类最常见的原发性脑肿瘤,到目前为止对其病因不清楚。近年来病毒在神经胶质瘤发生发展中的作用引起了多学科的广泛关注。有多篇报道在神经胶质瘤患者瘤组织中能检测到HHV-6 DNA的存在,但未能拿到病毒。人神经胶质瘤U251细胞是一种星形胶质瘤细胞株,具有星形胶质细胞部分特性,因此若能够建立HHV-6体外感染U251细胞模型,对研究HHV-6与神经胶质瘤的关系有指导意义。
本论文分三个部分,(一)HHV-6GS株在CBMCs中的培养扩增及病毒效价的滴定。通过PCR检测到HHV-6的DNA,间接免疫荧光检测到HHV-6抗原。病毒的滴度最终确定约为5×103TCID50/ml。(二)HHV-6感染神经胶质瘤U251细胞建立体外感染模型。结果发现HHV-6能感染U251细胞引起细胞病变,促进细胞增殖,使细胞周期发生改变及细胞因子IL-6分泌增加;成功建立了体外感染的模型。(三)对有丝分裂原活化蛋白激酶(mitogen-activated protein kinase , MAPK)信号通路的分支JNK和P38通路进行研究。结果发现在HHV-6的作用下磷酸化JNK和P38蛋白表达增加,病毒感染可能通过活化JNK和P38信号通路,引起肿瘤细胞的分化。
在成功建立HHV-6感染U251细胞体外模型的基础上,对HHV-6感染神经胶质瘤U251细胞的功能及机制作了初步研究,结果说明HHV-6与神经胶质瘤的发生发展存在一定的联系,为进一步研究神经胶质瘤的病毒病因和发病机理提供理论和实验依据。
Human herpes virus-6 (Human herpesvirus 6, HHV-6) is a kind of double-stranded DNA in human lymphocytes addicted virus. In 1986, Salahuddin et al were the first to isolate HHV-6 using peripheral blood mononuclear cells obtained from patients with lymphoid hyperplasia in the American Cancer Center. Two genetically distinct variants of the virus exist, HHV-6A and -6B. HHV-6 is aβ-herpesvirus related to HHV-7 and, to a lesser extent, human cytomegalovirus (HCMV). HHV-6 infection has a broad tropism, the main violations of CD4 + T cells, monocytes macrophages and glial cells. In 1988, Yamanishi et al confirmed HHV-6 is the pathogen of acute measles in infants and children (ES). Later, HHV-6 has been linked with many other kinds of diseases, including glioma, encephalitis, chronic fatigue syndrome, post-transplant infections and multiple sclerosis,although the significance of the associations is unclear.
Glioma is the most common primary brain malignant tumor. To date, the etiology is unclear.Recently, the role of virus in the development and progression of gliomas has caused widespread concern. A number of articles have reported that HHV-6 DNA can be detected by PCR in glioma tissue , but failed to get the virus. Human glioma U251 cell is a glioma cell line with some characteristics of astrocytes. So if it can be infected with HHV-6 in vitro, the study of relationship between HHV-6 and glioma can be carried.
The thesis contains three parts, (i) HHV-6 GS was inoculated in CBMCs, HHV-6 DNA and antigen were detected by PCR and IF respectively. Virus titer was determined as 5×103TCID50/ml. (ii) U251 cells can be infected with HHV-6 in vitro, resulting in CPE, cell proliferation, alteration of cell cycle and increasing the secretion of IL-6. (iii) The study of JNK and P38 pathway related todvision and differentiation of tumor cells. The results showed that HHV-6 increased the expression of the phosphorylated JNK and P38 proteins in U251 cells. Maybe the virus can induce the differentiation of tumor cells through activating JNK and P38 pathway.
The establishment of U251 cells infected with HHV-6 in vitro and the preliminary study of HHV-6 affecting the biological function of U251 cells and its mechanism illustrated that HHV-6 was linked to the occurrence and development of glioma,.It provides the theoretical and experimental basis to further study the etiology and pathogenesis of glioma.
引文
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