Global suppression of the host antiviral response by Ebola- and Marburgviruses:: Increased antagonism of the type I interferon response is associated with enhanced virulence
Global suppression of the host antiviral response by Ebola- and Marburgviruses:: Increased antagonism of the type I interferon response is associated with enhanced virulence
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DOI：
10.1128/jvi.80.6.3009-3020.2006
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发表时间：
2006-03-01
影响因子：
5.4
通讯作者：
Katze, MG
中科院分区：
文献类型：
--
作者：
Kash, JC;Mühlberger, E;Katze, MG
我们利用转录谱和生物信息学，通过表征感染扎伊尔埃博拉病毒（ZEBOV）、雷斯顿埃博拉病毒（REBOV）和马尔堡病毒（MARV）的人肝细胞中基因表达反应的调节，研究了丝状病毒感染对宿主细胞基因表达的影响。表达微阵列分析表明，丝状病毒感染导致免疫相关基因上调以及许多凝血和急性期蛋白下调。这些研究进一步揭示，丝状病毒毒力的一个共同特征是抑制关键的细胞抗病毒反应，包括 TLR、干扰素 (IFN) 调节因子 3 和 PKR 相关途径。我们进一步表明，与 REBOV 感染相比，ZEBOV 和 MARV 是 IFN 反应更有效的拮抗剂，并且抑制了在模拟感染的 IFN-α-2b 处理的细胞中观察到的大多数 IFN 刺激基因 (ISG) 的表达，REBOV 感染激活了超过 20% 的 ISG。最后，我们检查了用 IFN-α-2b 处理的丝状病毒感染细胞中 IFN 相关基因的表达。这些实验表明，在用 I 型 IFN 处理的模拟感染细胞中诱导的大多数基因在经过处理的 ZEBOV 和 MARV 感染的细胞中被拮抗，而相反，REBOV 感染导致 ISG 表达显着增加。 IFN 处理后 STAT1 和 -2 磷酸化的分析显示，MARV 的 STAT 磷酸化显着减少，但 ZEBOV 和 REBOV 则没有，表明不同的丝状病毒种类拮抗 IFN 信号传导途径可能涉及不同的机制。总而言之，这些研究表明 I 型干扰素反应的拮抗作用与丝状病毒毒力之间存在相关性。
We studied the effect of filovirus infection on host cell gene expression by characterizing the regulation of gene expression responses in human liver cells infected with Zaire Ebolavirus (ZEBOV), Reston Ebolavirus (REBOV), and Marburgvirus (MARV), using transcriptional profiling and bioinformatics. Expression microarray analysis demonstrated that filovirus infection resulted in the up-regulation of immune-related genes and the down-regulation of many coagulation and acute-phase proteins. These studies further revealed that a common feature of filovirus virulence is suppression of key cellular antiviral responses, including TLR-, interferon (IFN) regulatory factor 3-, and PKR-related pathways. We further showed that ZEBOV and MARV were more potent antagonists of the IFN response and inhibited the expression of most of the IFN-stimulated genes (ISGs) observed in mock-infected IFN-alpha-2b treated cells, compared to REBOV infection, which activated more than 20% of these ISGs. Finally, we examined IFN-related gene expression in filovirus-infected cells treated with IFN-alpha-2b. These experiments revealed that a majority of genes induced in mock-infected cells treated with type I IFN were antagonized in treated ZEBOV- and MARV-infected cells, while in contrast, REBOV infection resulted in a significant increase in ISG expression. Analysis of STAT1 and -2 phosphorylation following IFN treatment showed a significant reduction of STAT phosphorylation for MARV but not for ZEBOV and REBOV, indicating that different mechanisms might be involved in antagonizing IFN signaling pathways by the different filovirus species. Taken together, these studies showed a correlation between antagonism of type I IFN responses and filovirus virulence.