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

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毒等病原体。一些病毒能够颠覆自噬过程，甚至利用这些过程为自己谋利。其潜在的机制仍不清楚。许多病毒明显抑制自噬隔间的降解，即所谓的自噬小体。在流感病毒等重要病原体以及塞姆利基森林病毒(SFV)等模型病毒中发现了这一点。SFV属于甲型病毒属，与密切相关的高致病性基孔肯雅病毒(CHIKV)一起，基孔肯雅病毒是一种非常痛苦和危险的发热性疾病的病原体。本项目旨在利用细胞生物学、显微镜和生物化学的方法，确定这些甲型病毒影响感染细胞自噬的分子机制。首先，将重点关注已建立的模型病毒SFV，然后将发现扩展到致病性CHIKV。应该破译病毒是如何导致自噬小体积累的。特别是，它将检查哪些病毒蛋白是必需的，哪些细胞因素参与其中。对于SFV，人们发现病毒表面蛋白(“刺激性糖蛋白”)需要存在，但尚不清楚哪些是必需的，以及它们通过什么机制作用于自噬。此外，还将调查病毒如何干扰自噬的诱导，这是由关键的媒介mTOR调节的。该项目的结果将揭示甲型病毒感染细胞过程中自噬的一些机械原理。这将提供对自噬调节中病毒-细胞相互作用的更深层次的理解，这可能是治疗干预的一个目标。

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.