Autophagy in cells upon infection with alphaviruses (Semliki Forest virus, Chikungunya virus)

感染甲病毒（塞姆利基森林病毒、基孔肯雅病毒）后细胞中的自噬

• 批准号: 248331777
• 负责人: Dr. Bastian Thaa
• 金额: --
• 依托单位: Institut für Virologie
• 依托单位国家: 德国
• 项目类别: Research Fellowships
• 财政年份: 2013
• 资助国家: 德国
• 起止时间: 2012-12-31 至 2015-12-31
• 项目状态: 已结题
• 来源: https://gepris.dfg.de/gepris/projekt/248331777?language=en
• 关键词: Autophagy; cells; upon; infection; alphaviruses

Autophagy is an essential recycling process in every living cell. Autophagy occurs continuously, but is up-regulated under stress conditions. Autophagy also helps in cellular defence against pathogens such as viruses. Some viruses are able to subvert autophagic processes or even exploit them for their own benefit. The underlying mechanisms are still poorly understood.A number of viruses apparently inhibit the degradation of the autophagic compartments, so-called autophagosomes. This was found for important pathogens such as influenza virus as well as for model viruses such as Semliki Forest virus (SFV). SFV belongs to the genus Alphavirus, together with the closely related, highly pathogenic Chikungunya virus (CHIKV), the causative agent of a very painful and dangerous febrile illness. This project aims at identifying the molecular mechanisms by which these alphaviruses influence autophagy in infected cells using methods of cell biology, microscopy and biochemistry. First, the well-established model virus SFV will be in the focus, findings will then be extended to the pathogenic CHIKV. It shall be deciphered how the viruses cause the accumulation of autophagosomes. In particular, it will be examined which viral proteins are necessary and which cellular factors are involved. For SFV, it was found that the viral surface proteins ("spike glycoproteins") need to be present, but it is unclear which of them are required and by what mechanism they act on autophagy. Further, it will be investigated how the virus interferes with the induction of autophagy, regulated by the crucial mediator mTOR. The results from this project will reveal some mechanistic principles of autophagy during infection of cells with alphaviruses. This will provide a deeper understanding of the virus-cell interplay in the regulation of autophagy, which might represent a possible target of therapeutic intervention.

自噬是每个活细胞中必不可少的循环过程。自噬持续发生，但在应激条件下上调。自噬还有助于细胞防御病原体，如病毒。一些病毒能够破坏自噬过程，甚至利用它们为自己谋利。其内在机制目前仍不清楚，许多病毒明显抑制自噬区室（即所谓的自噬体）的降解。这在重要的病原体如流感病毒以及模型病毒如塞姆利基森林病毒（SFV）中发现。SFV属于甲病毒属，与密切相关的高致病性基孔肯雅病毒（CHIKV）一起，是非常痛苦和危险的发热性疾病的病原体。该项目旨在确定这些甲病毒影响感染细胞自噬的分子机制，使用细胞生物学，显微镜和生物化学的方法。首先，已建立的模型病毒SFV将成为焦点，研究结果将扩展到致病性CHIKV。病毒如何引起自噬体的积累将被破译。特别是，它将检查哪些病毒蛋白质是必要的，哪些细胞因子参与。对于SFV，发现病毒表面蛋白（“刺突糖蛋白”）需要存在，但尚不清楚它们中的哪些是必需的，以及它们通过什么机制作用于自噬。此外，还将研究病毒如何干扰由关键介质mTOR调节的自噬诱导。该项目的结果将揭示甲病毒感染细胞过程中自噬的一些机制原理。这将提供对病毒-细胞在自噬调节中的相互作用的更深入的理解，这可能代表治疗干预的可能靶点。

项目成果

Viral and cellular proteins containing FGDF motifs bind G3BP to block stress granule formation.

• DOI: 10.1371/journal.ppat.1004659
• 发表时间: 2015-02
• 期刊: PLoS pathogens
• 影响因子: 6.7
• 作者: Panas MD;Schulte T;Thaa B;Sandalova T;Kedersha N;Achour A;McInerney GM
• 通讯作者: McInerney GM

Differential Phosphatidylinositol-3-Kinase-Akt-mTOR Activation by Semliki Forest and Chikungunya Viruses Is Dependent on nsP3 and Connected to Replication Complex Internalization

Semliki 森林和基孔肯雅病毒对磷脂酰肌醇-3-激酶-Akt-mTOR 的差异激活依赖于 nsP3 并与复制复合体内化有关

• DOI: 10.1128/jvi.01579-15
• 发表时间: 2015
• 期刊: Journal of Virology
• 影响因子: 5.4
• 作者: Thaa B;Biasiotto R;Neuvonen M;Götte B;Rheinemann L;Mutso M;Varghese F;Balistreri G;Merits A;Ahola T;McInerney GM
• 通讯作者: McInerney GM