Research Network "FluResearchNet" - WP 03: Contribution of different cellular components of the innate immune system to the influenza virus-induced immune response in humans (FluResearchNet)

Basic data for this project

Description

The overwhelming rapid and mostly fatal course of human infections with the highly pathogenic avian influenza A virus of the H5N1 subtype suggests a significant contribution of the first line of defense to this septic disease. Major players of the innate immune system are myeloid cells as well as ECs. Since infections of birds with HPAIV are characterised by a severe septic-hemorrhagic inflammation in which ECs have a key role in the pathology we thoroughly characterized the role of ECs in human HPAIV infections during the first stage of this project. Moreover, infections with the H5N1 virus induce a strong cytokine burst. Therefore, in a second step we will focus our studies on the response of human monocytes upon infection with different HPAIV strains. Monocytes represent the most important first line producer of cytokines in most infections. We will delineate the genomic response of this cell type to infections with high and low pathogenic influenza virus strains in a comparative approach. This strategy allows the assignment of specific signalling pathways as well as involved transcriptional regulators. Consequently, we will be able to identify differences in the inflammatory response pattern of monocytes towards high- and low-pathogenic virus strains. A superior analysis of the network of influenza virus-induced signalling in human monocytes compared to human ECs then defines more detailed the role of each cell type in the entire immune response in humans. We seek to confirm our evaluation of human innate immune cells in animal models used in subprojects of the FluResearchNet. In collaboration with the projects #5 (Pleschka/Rautenschlein), #6 (Ludwig/Planz) and #7 (Schughart/Wagner) we intend to revise our data in mouse models. Finally, results should permit a prediction with regard to the most promising therapeutic approach to interrupt overwhelming infections with high pathogenic influenza viruses in humans.