Project 02

activation

• Principial Investigators:
  • TUD: Vasileia Ismini Alexaki &Andreas Linkermann
  • UZH: Wei-Lynn Wong & Annelies Zinkernagel 
• Students:
  • TUD: Nikolaos Nirakis (1st year-PhD student), Isabell Heber (Dr. med. student)

Background: Life and death decisions of infected epithelial cells are key to host defence and depend on metabolic cellular control and pathogen sensing by pattern recognition receptors (PRR). The pathways of regulated cell death necrosis, in particular necroptosis and pyroptosis, have evolutionarily emerged to defend the host against viral and bacterial infections, respectively, to initiate a fine-tuned immune response toward the infected tissue. Necroptosis is sensed by members of the TNF-receptor superfamily, PRRs such as Toll like receptors TLR3, TLR4 and TLR9 and intracellular nucleotide sensors. Necroptosis is mediated by the protein mixed lineage kinase domain like protein (MLKL) which was demonstrated to be involved in neutrophil extracellular trap (NET) formation, although MLKL-independent NET formation exists. NETs contribute towards the defence against group A Streptococcal infections and prevention of autoimmunity. As an alternative pathway to plasma membrane rupture, pyroptosis is a response downstream of inflammasome activation that is associated with maturation of specific pro-inflammatory cytokines. Beyond activation of the adaptive immune system by these cytokines, the response of cells undergoing necrosis is mainly driven by damage-associated molecular patterns (DAMPs) which stimulate the innate immune system. 
Importantly, innate immune cell priming, trained immunity and tolerance induction may be directly regulated by such bacteria-triggered cell death pathways. Along similar lines, we recently investigated triggers of trained immunity in murine models. There is compelling evidence from animal models demonstrating bacterial infection (vaccination with bacteria), e.g. Bacille Calmette–Guérin (BCG), fungi or helminth parasites protects against subsequent infections in a manner that is clearly independent of the adaptive immune system. Bacterial infections may cause complications, such as necrotizing fasciitis (NF), but the role of regulated necrosis in this condition is unknown. The team of this project aims at investigating the molecular network of bacteria-induced regulated necrosis and inflammasome activation to control cellular metabolism and necroinflammation.

The Linkermann group has strong expertise in mechanisms regulating cell death (49-55). The Alexaki group has strong expertise in immune-metabolism and glucocorticoid function. The Wei-Lynn Wong group has expertise in mechanisms underlying cell death signalling including inflammasome activation. The Zinkernagel group has strong expertise in acute and chronic bacterial infections as well as in mechanisms regulating cell death. Together as an interdisciplinary team, we hypothesize that regulated cell death, especially 
regulated necrosis, is at the pathophysiological centre of bacteria-induced control of metabolism and inflammation. We aim to test the role of regulated necrosis mechanistically (immune-metabolism of regulated necrosis), pathophysiologically (necroinflammation in the absence of inflammasomes) and during bacterial infection (the role of cell death and inflammasomes in murine models of group A Streptococcus infection). Many, if not all cell death pathways known so far can be pharmacologically inhibited, therefore we aim to unravel the underlying mechanisms as a basis 
for future drug development.

Aims: 1) Characterization of cell death specific innate immune cell metabolism
2) Assessment of the role of inflammasomes in bacteria-induced necroinflammation
3) Investigation of the role of cell death and inflammasome activation in group A
streptococcus infection

Added value through the collaboration between Dresden & Zurich: Combining the knowledge and technologies of cell death pathways, inflammasomes, metabolomics and Streptococcus infection, commonly resulting in a necrotic human phenotype, are exclusively possible in this consortium. In addition, access to human samples obtained from patients with necrotizing fasciitis will allow identifying the mechanisms of cell death in the pathophysiology of this disease.

Synergies: We will interact with projects 1 and 7 to assess the role of glucocorticoids in infection-induced necroptosis and pyroptosis and on the immunometabolic changes and cell necrosis in the adrenal gland upon infection. We will collaborate with projects 3 and 8 to examine how the metabolic state, dietary background and intervention may affect the induction of cell necrosis by infectious agents.