Research Network "FluResearchNet" - WP 06: The role of virus-induced signaling cascades in the replication of pathogenic influenza virus (FluResearchNet)

Basic data for this project

Description

Although a lot of novel information could be collected within the project, the complete picture how certain signaling pathways control cellular cytokine expression and directly or indirectly regulate viral replication and pathogenicity needs yet to be fully resolved. In a first part the proposed project, the achievements gained in the profiling studies will be driven to the level of functional analysis: We will use the data of the signaling profiling and global gene expression studies to further evaluate the function of individual NF-kB and p38 regulated genes (TNFa, IL-1b, GBP proteins) that are highly upregulated upon infection (project #6a). Furthermore we will assess the functional relevance of the transcription factors HMG1 and NF-ATC4 that have been identified to be specifically involved in HPAIV gene regulation (project #6a). In a joint attempt of project #6a and #6b the first promising results to use candidate inhibitors of NF-kB as antiviral agents will be driven forward in terms of analysis of the underlying molecular mechanism and the effectiveness in mouse and ferret models. project #6b will also provide the ferret model for studies of several other FluResearchNet partners on a commission base. In a second part of the project we will use the information gained and the methodology established to perform a detailed analysis of the signaling and apoptotic responses in cells (project #6a) and animals (project #6b) infected with the swine-origin influenza virus (S-OIV). Besides the signaling and gene expression profiling studies we will use recombinant S-OIV to determine the relevance of several pathogenicity factors that interfere with signaling and apoptosis, such as the NS1 protein and the PB1-F2 protein, that can be reconstituted in these viruses by mutation.