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

点击翻译按钮获取中文摘要

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.