Exploring the mechanisms of cytokine storm induction and systemic infection by highly pathogenic influenza viruses

Principal investigators

Dr. rer. nat.

Linda Brunotte

KFO 342 Principle investigator Univ.-Prof. Dr. rer. nat. Stefan Ludwig

Univ.-Prof. Dr. rer. nat.

Stephan Ludwig


Human infections with highly pathogenic avian Influenza A viruses (HPAIV) of the subtypes H5 and H7 often lead to severe disease caused by the excessive and imbalanced expression of pro-inflammatory cytokines. Viral, as well as host factors are suspected to function as the molecular drivers for the switch from local to systemic viral infections that give rise to severe tissue damage and multiple organ failure. However, fundamental knowledge about the identity of these factors and the underlying immunological mechanisms that could serve as a basis for the development of new clinical treatments to rebalance or prevent such excessive immune reactions during HPAIV infection is missing.

Similarly, confirmed biomarkers as early detection markers and indicators for therapeutic interventions to limit HPAIV-induced inflammatory responses have not been identified. Using the well-characterized virus SC35 (H7N7) and its relative SC35M (H7N7), that give rise to local or systemic infection, respectively, we will follow an integrative approach to provide a comprehensive analysis of the immune status of infected mice by combining the transcriptomic profiles from different organs and immune cells as well as infected human lung tissue. We will use our unique data set for the identification of specific biomarkers for systemically replicating HPAIV and analyze upregulation of known sepsis markers as well as factors involved in endothelial barrier leakage to deliver clinically relevant scientific knowledge for the development of new treatment options.

Picture showing a schematic description.

Phosphorylation of host factor TRIM28 regulates excessive expression of IFN-β and the pro-inflammatory cytokines IL-6 and IL-8 during HPAIV infection. Summary of the identified signaling cascade leading to the phosphorylation of TRIM28 during HPAIV infection. Viral RNA is recognized by PKR, which activates the stress-induced kinases p38 and MSK1 to facilitate TRIM28 S473 phosphorylation.

Our previous studies and phosphoproteome analysis have identified the viral polymerase as well as virus strain-specific induction of phosphomodification of several host proteins (e.g. TRIM28) as critical determinants. The proteins of the viral polymerase contain virus-specific immunomodulatory features and underlie strong adaptive pressure in humans. Based on a sequence alignment comparing relevant avian and HPAIV strains, we have identified unique amino acid signatures in the polymerases of HPAIV that may be involved in immune activation. In this project, we will determine the immunomodulatory potential of these signatures and generate recombinant viruses as a study model to elucidate the early processes (e.g. PRR activation) of overshooting immune responses by HPAIV.

We will further continue to characterize the roles of TRIM28, as well as the differentially modified phosphoproteins PEA-15 and NUP89 in the development of cytokine burst during HPAIV-infection. Experimental investigations by our lab have demonstrated that targeting phosphorylated host factors, or their activating kinases, can reduce the inflammatory response during HPAIV-infection and could serve as a novel therapeutic approach to prevent/rebalance uncontrollable immune reactions.

In this project, we will evaluate the therapeutic potential of three pre-investigated inhibitors of the cellular stress-induced MAP kinase p38, which has emerged as promising drug target in our previous studies, as repurposed drugs to prevent systemic viral spread and rebalance HPAIV-induced excessive immune reactions in mice and human lung tissue.

Project Team