Interferon-gamma-associated responses to woodchuck hepatitis virus infection in neonatal woodchucks and virus-infected hepatocytes.
Interferon-gamma-associated responses to woodchuck hepatitis virus infection in neonatal woodchucks and virus-infected hepatocytes.
复制标题
新生土拨鼠和病毒感染的肝细胞对土拨鼠肝炎病毒感染的干扰素-γ相关反应。
DOI：
10.1111/j.1365-2893.2004.00529.x
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发表时间：
2004
影响因子：
2.5
通讯作者：
Cote,PJ
中科院分区：
文献类型：
--
作者：
Wang,Y;Jacob,JR;Menne,S;Bellezza,CA;Tennant,BC;Gerin,JL;Cote,PJ
急性肝炎和土拨鼠肝炎病毒（WHV）感染的恢复涉及肝内干扰素-γ（IFN-γ）和肿瘤坏死因子-α（TNF-α）mRNA的表达增加。在本研究中，恢复与肝内主要组织相容性复合物1类（MHC 1）、β2微球蛋白、2′5′-寡腺苷酸合成酶（2′5′-OAS）和吲哚胺双加氧酶（IDO）mRNA表达增加相关。相比之下，急性WHV感染进展为慢性与肝脏中这些IFN-γ相关mRNA的表达减少相关。用IFN-γ表达质粒（pIFN-γ）转染来自WHV携带者的WHV感染的原代肝细胞（WPH），导致96 h内MHC 1、TNF-α、2′5′-OAS和IDO mRNA的剂量依赖性蓄积。 基于CD 3、CD 4、Fas配体、穿孔素和颗粒酶B mRNA的相对缺乏，在恢复肝脏中蓄积的T细胞标志物和免疫介导的细胞毒性在WPH中不明显。pIFN-γ和TNF-α表达质粒（pTNF-α）的表达不影响WPH中的总WHV RNA或完全双链WHV DNA，但各自减少了WHV DNA合成的一些复制中间体（RI）种类。用重组IFN-α蛋白处理的WPH具有较高的2′5′-OAS mRNA诱导倍数，与WHV RNA和主要RI种类的部分减少相关。因此，IFN-γ在载体WPH中的表达诱导了在恢复期土拨鼠肝脏中经常观察到的几种宿主反应，并通过TNF-α介导的非细胞溶解机制损害了WHV DNA合成的一个阶段。慢性WHV感染肝细胞中IFN-γ相关应答的局部增强可能促进治疗性抗病毒作用，但恢复期间明显的其他效应机制似乎是更完全清除WHV感染所必需的。
Acute hepatitis and recovery from woodchuck hepatitis virus (WHV) infection involves increased intrahepatic expression of interferon‐gamma (IFN‐γ) and tumour necrosis factor‐alpha (TNF‐α) mRNAs. In the present study, recovery correlated with increased intrahepatic expression of mRNAs for major histocompatibility complex class 1 (MHC1),β2‐microglobulin, 2′5′‐oligoadenylate synthetase (2′5′‐OAS), and indoleamine dioxygenase (IDO). By comparison, acute WHV infection progressing to chronicity was associated with diminished expression of these IFN‐γ‐associated mRNAs in liver. Transfection of WHV‐infected primary hepatocytes (WPH) from WHV carriers with an IFN‐γ‐expressing plasmid (pIFN‐γ) resulted in dose‐dependent accumulations of MHC1, TNF‐α, 2′5′‐OAS, and IDO mRNAs within 96 h. Markers of T cells and immune‐mediated cytotoxicity that accumulate in recovering liver were not apparent in WPH based on the relative lack of CD3, CD4, Fas ligand, perforin, and granzyme B mRNAs. Expression of pIFN‐γ, and TNF‐α‐expressing plasmid (pTNF‐α), did not affect total WHV RNA, or fully double‐stranded WHV DNA in WPH, but each reduced some of the replicative intermediate (RI) species of WHV DNA synthesis. WPH treated with recombinant IFN‐αprotein had a higher fold induction of 2′5′‐OAS mRNA associated with partial reductions in WHV RNAs and the major RI species. Thus, IFN‐γexpression in carrier WPH induced several host responses often observed in liver of recovering woodchucks, and impaired a stage of WHV DNA synthesis by a non‐cytolytic mechanism mediated by TNF‐α. Local enhancement of IFN‐γ‐associated responses in chronic WHV‐infected hepatocytes may promote therapeutic antiviral effects, but additional effector mechanisms evident during recovery appear necessary for more complete clearance of WHV infection.