Characterization of the role of the host protein NXF1 in the life cycle of ebolaviruses and other negative-sense RNA viruses

宿主蛋白 NXF1 在埃博拉病毒和其他负链 RNA 病毒生命周期中的作用的表征

基本信息

项目摘要

Ebolaviruses are zoonotic pathogens that cause severe hemorrhagic fevers with high case fatality rates. Until now no approved antiviral therapies are available, and while some experimental treatments show promise in clinical trials, they are antibody-based and thus most likely only active against specific ebolavirus species. Host factors represent a promising target for the development of indirectly active antivirals, since they often are shared between multiple virus species and sometimes even different virus families, so that targetting such host factors allows the development of broad-spectrum antivirals. Further, as these host factors are not encoded by viral genomes, the development of resistances against drugs targetting viral interactions with such host factors is much less likely than when directly targeting the virus. To faciliate such an approach, we have recently investigated the role of three host factors, i.e. NXF1, CAD and UAP56, for the life cycle of ebolaviruses in a DFG-funded project. The most interesting finding from this project was that NXF1 fulfills a novel role in the viral life cycle, and is most likely involved in the export of viral mRNAs from inclusion bodies, which are viral structures in the cytoplasm where virus genome replication and transcription takes place. Further, we could show that this host factor is also important for another negative-sense RNA virus, i.e. Junin virus, which causes severe hemorrhagic fevers in South America. However, currently we do not know whether NXF1 plays the same role in the life cycle of this virus than it does for ebolaviruses. We now propose to continue our studies on NXF1, and to investigate the molecular details of its function for ebolaviruses, in order to define molecular targets for intervention, which allow us to destroy the interaction of NXF1 with ebolaviruses, while preserving its cellular funtion. For this we will map the interaction sites on NXF1 and its viral interaction partner NP, assess which other cellular factors are involved in the process of mRNA export from inclusion bodies, and then analyse the binding dynamics of viral mRNA and the various cellular and viral factors. Further, we want to expand our studies onto Junin virus as a representative for other negative-sense RNA viruses, and assess whether NXF1 might represent a shared host factor and thus a suitable target for the development of broad-spectrum antivirals. For this we will take advantage of the same work flow we have already succesfully used for ebolaviruses, and adapt and apply these methods to Junin virus in order to identify viral interaction partners, and to characterizeing the function of NXF1 for this virus. These studies will provide an important basis for the development of indirectly acting antivirals against ebolaviruses, and potentially also other negative-sense RNA viruses.
埃博拉病毒是人畜共患病原体,可引起严重出血热,病死率高。到目前为止,还没有批准的抗病毒疗法,虽然一些实验性治疗在临床试验中显示出希望,但它们是基于抗体的,因此很可能只对特定的埃博拉病毒物种有效。宿主因子代表了开发间接活性抗病毒药物的有希望的靶点,因为它们通常在多个病毒物种之间共享,有时甚至在不同的病毒家族之间共享,因此靶向这些宿主因子允许开发广谱抗病毒药物。此外,由于这些宿主因子不是由病毒基因组编码的,因此针对病毒与这些宿主因子相互作用的药物产生耐药性的可能性比直接针对病毒时要小得多。为了促进这种方法,我们最近在DFG资助的项目中研究了三个宿主因子,即NXF1,CAD和UAP56对埃博拉病毒生命周期的作用。该项目最有趣的发现是NXF1在病毒生命周期中发挥了新的作用,并且最有可能参与从包涵体中输出病毒mRNA,包涵体是细胞质中的病毒结构,病毒基因组复制和转录发生。此外,我们还可以证明,这种宿主因子对另一种负义RNA病毒也很重要,即在南美洲引起严重出血热的朱宁病毒。然而,目前我们还不知道NXF1在这种病毒的生命周期中是否发挥着与埃博拉病毒相同的作用。我们现在建议继续我们对NXF1的研究,并研究其对埃博拉病毒功能的分子细节,以确定干预的分子靶点,这使我们能够破坏NXF1与埃博拉病毒的相互作用,同时保留其细胞功能。为此,我们将绘制NXF1及其病毒相互作用伴侣NP上的相互作用位点,评估哪些其他细胞因子参与了mRNA从包涵体输出的过程,然后分析病毒mRNA与各种细胞和病毒因子的结合动力学。此外,我们希望将我们的研究扩展到朱宁病毒作为其他负义RNA病毒的代表,并评估NXF1是否可能代表一个共享的宿主因子,从而成为开发广谱抗病毒药物的合适靶点。为此,我们将利用我们已经成功用于埃博拉病毒的相同工作流程,并将这些方法适应和应用于朱宁病毒,以鉴定病毒相互作用伴侣,并表征NXF 1对该病毒的功能。这些研究将为开发针对埃博拉病毒以及潜在的其他负义RNA病毒的间接作用抗病毒药物提供重要基础。

项目成果

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Privatdozent Dr. Thomas Hoenen其他文献

Privatdozent Dr. Thomas Hoenen的其他文献

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{{ truncateString('Privatdozent Dr. Thomas Hoenen', 18)}}的其他基金

Biology of ebolavirus inclusion bodies
埃博拉病毒包涵体的生物学
  • 批准号:
    452208680
  • 财政年份:
  • 资助金额:
    --
  • 项目类别:
    Research Grants

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