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J Immunol:NF-KB参与抗HBV感染天然免疫反应

来源:生物谷 2016-06-16 09:36

 

2016年6月16日 讯 /生物谷BIOON/ --细胞内的天然免疫反应是抵抗外源病毒感染的第一道防线,其中I型与III型干扰素起着关键的作用。目前对于抗RNA病毒的免疫反应机制了解的比较深入,但对于肝脏抵抗DNA病毒感染的机制仍不清楚。此前研究发现,DNA病毒能够直接通过DNA或RNA中间物引起NF-KB的激活,但这一信号对于抗HBV免疫反应以及干扰素的产生是否具有联系仍不清楚。为了研究清楚上述问题,来自迈阿密大学医学院的Emmanuel Thomas课题组进行了深入的研究,相关结果发表在最近一期的《Journal of Immunology》杂志上。

HBV是一类DNA病毒,在感染过程中能够通过宿主细胞中的RNA聚合酶活性产生RNA中间产物。一些研究认为HBV在感染肝脏细胞的过程中并不会引发明显的天然免疫基因表达,而且肝脏损伤似乎是由长期的抗感染免疫反应所导致的。然而,另外一些研究发现HBV在后天免疫反应开始之前就可以被清除掉,这表明抗病毒天然免疫反应对于HBV的清除具有重要的作用。

在这项研究中,首先,作者通过体外HBV感染试验证明肝脏细胞在受到HBV感染之后能够快速地产生CXCL10以及CCL5等基因的表达。进一步,作者通过一种叫做entecavir的小分子药物抑制HBV的复制,然而这一处理没有影响HBV感染引发的上述因子的表达。作者通过芯片技术分析了HBV感染后肝脏细胞基因的表达谱变化,结果显示,包括CCL5以及CXCL10在内的多个基因表达都发生了变化。

之后,作者发现病毒的DNA以及 poly(dA:dT) 、poly(dG:dC)等均能够引起肝脏细胞表达趋化因子以及干扰素,而通过将TBK或者IRF3的活性抑制,则能够有效抑制上述基因的表达。

进一步,作者发现DNA以及其它类似物(ISD、2-3 cGAMP)均能够引起IRF的快速活化,表明DNA确实能够引发抗病毒免疫反应。

接下来,作者检测了已知的DNA信号通路是否参与了肝脏细胞抗病毒感染的免疫激活,结果显示,IFI16以及AMI2等均参与了肝脏细胞抗HBV感染的免疫反应。通过RNA干扰试验,作者发现IKKgamma的活性抑制能够有效降低抗HBV感染的免疫反应效应。这说明NF-KB参与了抗HBV天然免疫过程。(生物谷Bioon.com)

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doi: 10.4049/jimmunol.1502677

PMC:

PMID:

Hepatitis B Virus and DNA Stimulation Trigger a Rapid Innate Immune Response through NF-κB

Masato Yoneda, Jinhee Hyun, Silvia Jakubski, Satoru Saito, Atsushi Nakajima, Eugene R. Schiff, and Emmanuel Thomas

Cell-intrinsic innate immunity provides a rapid first line of defense to thwart invading viral pathogens through the production of antiviral and inflammatory genes. However, the presence of many of these signaling pathways in the liver and their role in hepatitis B virus (HBV) pathogenesis is unknown. Recent identification of intracellular DNA-sensing pathways and involvement in numerous diverse disease processes including viral pathogenesis and carcinogenesis suggest a role for these processes in HBV infection. To characterize HBV-intrinsic innate immune responses and the role of DNA- and RNA-sensing pathways in the liver, we used in vivo and in vitro models including analysis of gene expression in liver biopsies from HBV-infected patients. In addition, mRNA and protein expression were measured in HBV-stimulated and DNA-treated hepatoma cell lines and primary human hepatocytes. In this article, we report that HBV and foreign DNA stimulation results in innate immune responses characterized by the production of inflammatory chemokines in hepatocytes. Analysis of liver biopsies from HBV-infected patients supported a correlation among hepatic expression of specific chemokines. In addition, HBV elicits a much broader range of gene expression alterations. The induction of chemokines, including CXCL10, is mediated by melanoma differentiation-associated gene 5 and NF-κB-dependent pathways after HBV stimulation. In conclusion, HBV-stimulated pathways predominantly activate an inflammatory response that would promote the development of hepatitis. Understanding the mechanism underlying these virus-host interactions may provide new strategies to trigger noncytopathic clearance of covalently closed circular DNA to ultimately cure patients with HBV infection.

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