马立克氏病病毒诱导的免疫应答基因表达谱及miRNA对肿瘤发生的调节作用
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摘要
马立克氏病(MD)是由高度细胞相关的免疫抑制性致癌α-疱疹病毒—马立克氏病病毒(MDV)引起鸡的一种淋巴组织增生性疾病,MDV在B细胞内限制性产生感染,感染后7天左右(7 dpi)在CD4+ T淋巴细胞中潜伏感染,持续两个星期之后病毒重新激活并诱导肿瘤的发生、发展。潜伏感染的T淋巴细胞病毒从皮肤和羽毛毛囊上皮细胞,释放含囊膜的病毒颗粒到周围环境中。感染转化的CD4+ T细胞含有马立克氏病病毒基因组,通过血液迁移并在皮肤、内脏器官和外周神经建立淋巴瘤。
在本研究中,利用实时定量RT-PCR方法对rMd5和rMd5Δmeq在5 dpi的鸡脾脏组织中免疫和非免疫相关基因进行了研究。结果表明,rMd5和rMd5Δmeq均能够对感染鸡引起强烈的免疫反应,而meq基因对宿主基因表达没有显著影响。同时发现重组鸡痘病毒rFPV+meq感染的鸡胚胎成纤维细胞中Bcl-2的转录活性降低,表明单独的meq基因不能阻碍鸡痘病毒诱导的细胞凋亡,相反起着加速凋亡作用。
基因芯片的数据也支持上述分析,并显示meq基因在21 dpi对于病毒的重激活和复制起着重要作用。另外,rMd5和rMd5Δmeq重组病毒感染都涉及宿主免疫应答诱导的IFN-α/β信号转导通路以及干扰素的抗病毒作用途径,这种免疫应答作用在病毒感染5dpi被激活,而在21 dpi迅速被抑制。此外,通过实时定量RT-PCR技术对感兴趣的基因,如MMP-13,MX,IFN-γ,VLIG-1,Bcl2l14和Bu-1a进行了测定,阐述了它们在马立克氏病病毒感染后的促/抗肿瘤或细胞凋亡过程中的作用。所有的结果表明,在MDV感染初期,鸡体免疫系统具有很强的抗病毒、抗肿瘤及促细胞凋亡作用,但随着MDV感染进程,经过潜伏期的逃逸至病毒的重新激活,宿主的抗病毒及抗肿瘤作用明显受到抑制,这便为MDV病毒的后期感染和肿瘤发生、发展创造了便利条件。
为了阐述miRNA在MDV诱导肿瘤发生过程中所扮演的角色,对gga-miR-181a、gga-miR-21以及相关基因如Fas L、FIGN、HOXA11等也进行了一系列的测定,以确定它们在诱导MSB-1细胞凋亡、细胞增殖过程中相互关系。结果表明,gga-miR-181a和gga-miR-21都与细胞的程序性死亡成正相关关系。此外,FIGN和HOXA11具有很强的抗凋亡和促进肿瘤细胞增殖的能力,至少是在CD4+ T淋巴瘤细胞中,并且这种作用受gga-miR-21调节。
Marek’s disease (MD) is a lymphoproliferative disease of domestic chickens caused by a highly cell-associated immunosuppressive oncogenicα-herpes virus, MD virus (MDV). After a brief burst of productive/restrictive infection in B cells, a latent infection in CD4+ T lymphocytes occurs at about 7 days post infection (dpi) that lasts up to two weeks prior to virus reactivation and tumor development. The latently infected T lymphocytes are the means of virus dissemination to the skin and feather follicle epithelial cells, where fully infections enveloped cell-free virus particles are produced and released into the environment. The subsets of latently infected transformed CD4+ T cells that harbor MDV genome, migrate through the blood stream, and establish lymphomas in the skin, visceral organs, and peripheral nerves.
In this study, the seletected immune- and nonimmune-related genes were tested in the spleen tissues of rMd5- and rMd5?meq-infected chickens at 5 dpi by the Real-Time RT-PCR methods. The results showed that both rMd5 and rMd5?meq can cause strong immune response in the infected chickens, and the meq gene had no significant impact on the gene expression profile. In addition, a reduction in the transcriptional activity of Bcl-2 in recombinant fowlpox virus (rFPV)+meq-infected chicken embryonic fibroblasts suggested that meq alone did not impede, but accelerated FPV-induced apoptosis.
The microarray data also supported the profile analysis above, and showed the meq gene was important for the virus reactivation and replication at 21 dpi. While, Both rMd5- and rMd5?meq-infection involved in the host immune respose-IFNα/βsignaling pathway and antivirial action of interferons which were activated and suppressed, repectively at 5dpi and 21 dpi. Also, those interested genes, such as MMP-13, Mx, IFN-γ, VLIG-1, Bcl2l14 and Bu-1a, were tested by Real-Time RT-PCR to illuminate the roles in pro/anti– tumor or–apoptosis progress with the MDV infection. All the results indicated that the immune system of chicken possessed a strong antiviral, anti-tumor and pro-apoptosis effection at the initial MDV infection phase, but these kinds of host abilities were supressed immediately after the latence infection and reactivation of virus, which created a great condition for virus infection and tumor developing in the later period of MDV activity.
In order to illuminate the miRNA roles in the MDV-induced tumor developing, gga-miR-181a, gga-miR-21, and also the related genes, such as Fas L, FIGN, HOXA11, and etc, were choosed to determine their relationship during the progress of MSB-1 cell induced to apoptosis or proliferation. The results indicated that both gga-miR-181a and -21 were involved in and correlated positively with the programmed cell death. In addition, FIGN and HOXA11 possessed great abilities of anti-apoptosis and promotion of tumor cell proliferation, which were regulated by gga-miR-21, at least, in the CD4+ T lymphoma.
在本研究中,利用实时定量RT-PCR方法对rMd5和rMd5Δmeq在5 dpi的鸡脾脏组织中免疫和非免疫相关基因进行了研究。结果表明,rMd5和rMd5Δmeq均能够对感染鸡引起强烈的免疫反应,而meq基因对宿主基因表达没有显著影响。同时发现重组鸡痘病毒rFPV+meq感染的鸡胚胎成纤维细胞中Bcl-2的转录活性降低,表明单独的meq基因不能阻碍鸡痘病毒诱导的细胞凋亡,相反起着加速凋亡作用。
基因芯片的数据也支持上述分析,并显示meq基因在21 dpi对于病毒的重激活和复制起着重要作用。另外,rMd5和rMd5Δmeq重组病毒感染都涉及宿主免疫应答诱导的IFN-α/β信号转导通路以及干扰素的抗病毒作用途径,这种免疫应答作用在病毒感染5dpi被激活,而在21 dpi迅速被抑制。此外,通过实时定量RT-PCR技术对感兴趣的基因,如MMP-13,MX,IFN-γ,VLIG-1,Bcl2l14和Bu-1a进行了测定,阐述了它们在马立克氏病病毒感染后的促/抗肿瘤或细胞凋亡过程中的作用。所有的结果表明,在MDV感染初期,鸡体免疫系统具有很强的抗病毒、抗肿瘤及促细胞凋亡作用,但随着MDV感染进程,经过潜伏期的逃逸至病毒的重新激活,宿主的抗病毒及抗肿瘤作用明显受到抑制,这便为MDV病毒的后期感染和肿瘤发生、发展创造了便利条件。
为了阐述miRNA在MDV诱导肿瘤发生过程中所扮演的角色,对gga-miR-181a、gga-miR-21以及相关基因如Fas L、FIGN、HOXA11等也进行了一系列的测定,以确定它们在诱导MSB-1细胞凋亡、细胞增殖过程中相互关系。结果表明,gga-miR-181a和gga-miR-21都与细胞的程序性死亡成正相关关系。此外,FIGN和HOXA11具有很强的抗凋亡和促进肿瘤细胞增殖的能力,至少是在CD4+ T淋巴瘤细胞中,并且这种作用受gga-miR-21调节。
Marek’s disease (MD) is a lymphoproliferative disease of domestic chickens caused by a highly cell-associated immunosuppressive oncogenicα-herpes virus, MD virus (MDV). After a brief burst of productive/restrictive infection in B cells, a latent infection in CD4+ T lymphocytes occurs at about 7 days post infection (dpi) that lasts up to two weeks prior to virus reactivation and tumor development. The latently infected T lymphocytes are the means of virus dissemination to the skin and feather follicle epithelial cells, where fully infections enveloped cell-free virus particles are produced and released into the environment. The subsets of latently infected transformed CD4+ T cells that harbor MDV genome, migrate through the blood stream, and establish lymphomas in the skin, visceral organs, and peripheral nerves.
In this study, the seletected immune- and nonimmune-related genes were tested in the spleen tissues of rMd5- and rMd5?meq-infected chickens at 5 dpi by the Real-Time RT-PCR methods. The results showed that both rMd5 and rMd5?meq can cause strong immune response in the infected chickens, and the meq gene had no significant impact on the gene expression profile. In addition, a reduction in the transcriptional activity of Bcl-2 in recombinant fowlpox virus (rFPV)+meq-infected chicken embryonic fibroblasts suggested that meq alone did not impede, but accelerated FPV-induced apoptosis.
The microarray data also supported the profile analysis above, and showed the meq gene was important for the virus reactivation and replication at 21 dpi. While, Both rMd5- and rMd5?meq-infection involved in the host immune respose-IFNα/βsignaling pathway and antivirial action of interferons which were activated and suppressed, repectively at 5dpi and 21 dpi. Also, those interested genes, such as MMP-13, Mx, IFN-γ, VLIG-1, Bcl2l14 and Bu-1a, were tested by Real-Time RT-PCR to illuminate the roles in pro/anti– tumor or–apoptosis progress with the MDV infection. All the results indicated that the immune system of chicken possessed a strong antiviral, anti-tumor and pro-apoptosis effection at the initial MDV infection phase, but these kinds of host abilities were supressed immediately after the latence infection and reactivation of virus, which created a great condition for virus infection and tumor developing in the later period of MDV activity.
In order to illuminate the miRNA roles in the MDV-induced tumor developing, gga-miR-181a, gga-miR-21, and also the related genes, such as Fas L, FIGN, HOXA11, and etc, were choosed to determine their relationship during the progress of MSB-1 cell induced to apoptosis or proliferation. The results indicated that both gga-miR-181a and -21 were involved in and correlated positively with the programmed cell death. In addition, FIGN and HOXA11 possessed great abilities of anti-apoptosis and promotion of tumor cell proliferation, which were regulated by gga-miR-21, at least, in the CD4+ T lymphoma.
引文
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