MAC’n FLU: Deciphering the macrophage-influenza A virus interactions, host responses, and infection control.

• Applicant: Dr. Kevin Ciminski
• Subject Area: Virology
• Term: since 2025
• Project identifier: Deutsche Forschungsgemeinschaft (DFG) - Project number 570717242

Influenza A viruses (IAVs) are highly infectious pathogens that are well-known for their ability to cross the animal-human species barrier and cause severe disease. The exact events leading to severe disease after zoonotic infection with IAVs of animal origin, such as avian H5N1 viruses, are not fully understood. However, several lines of evidence suggest that infection of alveolar macrophages triggers an excessive release of pro-inflammatory cytokines that is central to disease development. Yet it is completely unclear why these severe outcomes occur specifically after infection with avian H5N1, whereas they are rarely observed after infection with seasonal human H1N1 viruses. Using single-cell sequencing, we have now shown that infection of primary human macrophages with different avian H5N1 viruses leads to a strong transcriptional activation of pro-inflammatory pathways and to the induction of different forms of cell death. In contrast, infection with human H1N1 or the bat-derived IAV H18N11, which naturally infects and replicates in immune cells such as macrophages, causes transcriptional changes in metabolic pathways but little cell death. Based on these observations, we hypothesize the existence of an IAV-dependent "macrophage host response". The overall goal of this research project is to use bioinformatics models to identify the cellular pathways and gene sets responsible for the respective host responses in human macrophages, and to determine the viral factors that trigger these programs by combining reverse genetics, cell biological methods, RNA sequencing and phosphoproteome analysis. We will use these findings to develop translational intervention approaches to specifically inhibit macrophage-mediated inflammation. We will extend our analyses to primary bat macrophages from the Jamaican fruit bat, as these represent the natural tropism of bat IAV H18N11. In the final part of the project, we will characterize the spatio-temporal infection dynamics and the induced immune response in the tissues of H18N11-infected Jamaican fruit bats using multiplex RNA in situ hybridization to investigate the consequences of macrophage infection in vivo, taking into account cellular heterogeneity. We expect that this cutting-edge comparative viral immunology project and the associated dissection of macrophage host responses will significantly advance our understanding of virus-host interactions and the role of macrophages during IAV infection.

• DFG Programme: Emmy Noether Independent Junior Research Groups
• International Connection: USA
• Cooperation Partner: Professor Dr. Tony Schountz