VirMEDACO

Cellular homeostasis requires permanent cellular surveillance and response to internally and externally inflicted insults. Such insults include the DNA damage response (DDR) and the unfolded protein response (UPR) directed against DNA or protein damage e.g. caused by invading pathogens. Membrane damage is another insult to cells but the resulting membrane damage response (MDR) is much less understood. The Aim of this proposal is to use an integrative approach to study how viruses inflict membrane damage as port of entry into cells and how they seek control over the cellular response including antiviral autophagy and interferon signaling. The approach is based on emergent technologies in cellular biology, biophysics and optics. As model system we use adenoviruses (AdV) that rupture endosomes upon cell entry to escape into the cytosol. The project will be addressed by a consortium of highly trained experts with complementing expertise in cell biology, biophysics, structural biology, solid-state NMR, cryo electron-microscopy (cryoEM) and cryo electron-tomography (cryoET) to be used with a combination of depletion/reconstitution and infection assays. Structural and high-end imaging techniques will serve to characterize the in situ organization of the virus induced membrane penetration to decipher the underlying structural mechanisms of the molecular interplay involved in virus entry at the atomic level. Furthermore, we will apply current knowledge together with unbiased methods to identify essential factors involved in viral control of the membrane damage response to suppress antiviral autophagy and interferon signaling. Taken together, we will identify critical (novel) regulators and viral strategies to seek control of the membrane damage response, which maybe relevant to other disease models involving membrane damage.