Inhibition of different lassa virus strains by alpha and gamma interferons and comparison with a less pathogenic arenavirus
Inhibition of different lassa virus strains by alpha and gamma interferons and comparison with a less pathogenic arenavirus
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DOI：
10.1128/jvi.78.6.3162-3169.2004
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发表时间：
2004-03-01
影响因子：
5.4
通讯作者：
Günther, S
中科院分区：
文献类型：
--
作者：
Asper, M;Sternsdorf, T;Günther, S
拉沙病毒的高致病性被认为涉及对干扰素（IFN）作用的抗性。我们已经分析了α干扰素（IFN-α），IFN-γ和肿瘤坏死因子α（TNF-α）对拉沙病毒复制的影响，与相关的，但致病性较低的淋巴细胞性脉络丛脑膜炎病毒（LCMV）相比。对从患有轻度至暴发性拉沙热的人中分离的三种低传代拉沙病毒株（AV、NL和CSF）进行了测试。在Huh 7和Vero细胞中，IFN-α和IFN-γ抑制拉沙病毒复制，但不抑制TNF-α。拉沙病毒分离株的IFN敏感性程度与人类患者的疾病严重程度无关。此外，观察到拉沙病毒和LCMV（CH-5692、Armstrong和WE株）的细胞因子效应相似。为了解决干扰素的作用机制，我们使用的细胞系中，干扰素刺激的蛋白质早幼粒细胞白血病蛋白（PML）和Sp100的过表达可以诱导。这两种蛋白质都存在于PML体中，PML体是LCMV和拉沙病毒Z蛋白的细胞靶点。PML或Sp100的过表达不影响任一病毒的复制。这与先前发现PML敲除在体外和体内促进LCMV复制一起（M. Djavani，J. Rodas，I. S. Lukashevich，D.作者声明：A. L. Borden和M. S. Salvato，J. Virol. 75：6204-6208，2001; W. V. Bonilla，D. D. Pinschewer，P. Klenerman，V. Gaboli，P. P. Pandolfi，R. M. Zinkernagel，M. S. Salvato和H. Hengartner，J. Virol. 76：3810-3818，2002）描述了PML作为抗病毒途径内的介体而不是作为直接效应蛋白。总之，与LCMV相比，拉沙病毒的高致病性可能不是由于对IFN-α或IFN-γ作用的抗性增加。这两种细胞因子都抑制复制，这与针对拉沙热的抗病毒策略的设计相关，目的是增强IFN应答。
The high pathogenicity of Lassa virus is assumed to involve resistance to the effects of interferon (IFN). We have analyzed the effects of alpha IFN (IFN-alpha), IFN-gamma, and tumor necrosis factor alpha (TNF-alpha) on replication of Lassa virus compared to the related, but less pathogenic, lymphocytic choriomeningitis virus (LCMV). Three low-passage Lassa virus strains (AV, NL, and CSF), isolated from humans with mild to fulminant Lassa fever, were tested. Lassa virus replication was inhibited by IFN-alpha and IFN-gamma, but not TNF-alpha, in Huh7 and Vero cells. The degree of IFN sensitivity of a Lassa virus isolate did not correlate with disease severity in human patients. Furthermore, cytokine effects observed for Lassa virus and LCMV (strains CH-5692, Armstrong, and WE) were similar. To address the mechanisms involved in the IFN effect, we used cell lines in which overexpression of IFN-stimulated proteins promyelocytic leukemia protein (PML) and Sp100 could be induced. Both proteins reside in PML bodies, a cellular target of the LCMV and Lassa virus Z proteins. Overexpression of PML or Sp100 did not affect replication of either virus. This, together with the previous finding that PML knockout facilitates LCMV replication in vitro and in vivo (M. Djavani, J. Rodas, I. S. Lukashevich, D. Horejsh, P. P. Pandolfi, K. L. Borden, and M. S. Salvato, J. Virol. 75:6204-6208, 2001; W. V. Bonilla, D. D. Pinschewer, P. Klenerman, V. Rousson, M. Gaboli, P. P. Pandolfi, R. M. Zinkernagel, M. S. Salvato, and H. Hengartner, J. Virol. 76:3810-3818, 2002), describes PML as a mediator within the antiviral pathway rather than as a direct effector protein. In conclusion, the high pathogenicity of Lassa virus compared to LCMV is probably not due to increased resistance to the effects of IFN-alpha or IFN-gamma. Both cytokines inhibit replication which is relevant for the design of antiviral strategies against Lassa fever with the aim of enhancing the IFN response.