Project description:Seasonal epidemics of influenza A virus in the human population are a major cause of severe illness and are of high socio-economic relevance. For the design of effective anti-viral therapies, a detailed knowledge of cellular pathways perturbed by virus infection is critical. We performed comprehensive expression and organellar proteomics experiments using A549, Calu-1 and NCI-H1299 cells to identify new protein targets and cellular pathways affected by influenza A virus.
Project description:Seasonal epidemics of influenza A virus are a major cause of severe illness and are of high socio-economic relevance. For the design of effective anti-viral therapies, a detailed knowledge of cellular pathways perturbed by virus infection is critical. We performed comprehensive expression and organellar proteomics experiments to identify new protein targets and cellular pathways affected by influenza A virus. Type I as well as type II interferon pathways were upregulated upon infection, affecting amongst others poly ADP-ribose polymerase transcription factors and ubiquitin-like modifiers. In addition, influenza A virus had a major influence on the subcellular localization of proteins and complexes. The vesicular compartment appeared expanded upon infection and in particular the composition of autophagsomes was altered, virus infection leading to targeting of ribosomes to autophagosomes.
Project description:Although annual epidemics of seasonal influenza affect around 10% of the global population, current treatment options are limited and development of new antivirals is urgently needed. Here, using state-of-the-art quantitative phosphoproteomics, we reveal the unique phosphoproteome dynamics that occur in the host cell within minutes of influenza A virus (IAV) infection. Based on this virus-induced phosphorylation signature, we uncover cellular kinases required for the observed signalling pattern and find that inhibition of selected candidates, such as the G protein-coupled receptor kinase 2 (GRK2), leads to decreased IAV replication. As GRK2 has emerged as drug target in heart disease, we focus on its role in IAV infection and show that it is required for viral entry at the stage of uncoating. Replication of seasonal and pandemic IAVs is severely decreased by specific GRK2 inhibitors in primary human airway cultures and in an animal model. Our study reveals the IAV-induced changes to the cellular phosphoproteome and identifies GRK2 as a crucial node of the kinase network that enables IAV replication.
Project description:Whole-genome data was developed from influenza virus infected A549 cells to better characterize the effect of C646 on influenza virus infection
