Asper Marcel, Sternsdorf Thomas, Hass Meike, Drosten Christian, Rhode Antje, Schmitz Herbert, Günther Stephan
Department of Virology, Bernhard-Nocht-Institute of Tropical Medicine, 20359 Hamburg, Germany.
J Virol. 2004 Mar;78(6):3162-9. doi: 10.1128/jvi.78.6.3162-3169.2004.
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.
拉沙病毒的高致病性被认为与对干扰素（IFN）作用的抗性有关。我们分析了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，并与相关但致病性较低的淋巴细胞性脉络丛脑膜炎病毒（LCMV）进行了比较。对从患有轻度至暴发性拉沙热的人类中分离出的三株低传代拉沙病毒株（AV、NL和CSF）进行了测试。在Huh7和Vero细胞中，IFN-α和IFN-γ可抑制拉沙病毒的复制，但TNF-α不能。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，观察到的拉沙病毒和LCMV（CH-5692、阿姆斯特朗和WE株）的细胞因子效应相似。为了探究IFN作用所涉及的机制，我们使用了可诱导IFN刺激蛋白早幼粒细胞白血病蛋白（PML）和Sp100过表达的细胞系。这两种蛋白都存在于PML小体中，PML小体是LCMV和拉沙病毒Z蛋白的细胞靶点。PML或Sp100的过表达均不影响两种病毒的复制。这与之前的发现一致，即PML基因敲除在体外和体内均促进LCMV复制（M. Djavani、J. Rodas、I. S. Lukashevich、D. Horejsh、P. P. Pandolfi、K. L. Borden和M. S. Salvato，《病毒学杂志》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和H. Hengartner，《病毒学杂志》76:3810 - 3818，2002），这表明PML是抗病毒途径中的一种介质，而非直接效应蛋白。总之，与LCMV相比，拉沙病毒的高致病性可能并非由于对IFN-α或IFN-γ作用的抗性增加。这两种细胞因子均抑制病毒复制，这对于旨在增强IFN反应的抗拉沙热抗病毒策略的设计具有重要意义。
