Research Area A

The metabolism of infections.

 

Project 1: Chart the comprehensive metabolic rewiring of macrophages upon infection (Prof. Dr. Christian Frezza).

This project is based on the extensive evidence that the metabolism of macrophages is rewired upon infection, and this rewiring is tightly linked to the downstream effector functions of macrophages in clearing the infection. For instance, we and others have demonstrated that during inflammation macrophages increase the mitochondrial metabolites succinate and itaconate, which have signaling functions and, in particular itaconate, can also act as an antimicrobial molecule. However, recent data have revealed that other metabolic pathways are deregulated in macrophages upon inflammation, including nucleotides and cyclic nucleotides, and very recently the purine nucleotide cycles. Their role in macrophage function remains unclear. The central objective of this project is to chart the comprehensive metabolic rewiring of macrophages upon infection and during the resolution of the insult, upon different inflammatory stimuli and pathogens. Our main focus will be nucleotide metabolism and how its deregulation participates in macrophage function. i-HEAD will provide a perfect scientific environment to address such overarching questions controlling immunity and infection and will offer unique collaborations and expertise to address both basic science and therapeutic questions focused on macrophage function. Therefore, we aim to investigate the following research questions:

• characterize the dysregulation of nucleotide and cyclic nucleotide metabolism in mousemacrophages exposed to different inflammatory stimuli using a metabolomics approach.
• manipulation of relevant metabolic pathways to modulate the inflammatory response in mouse macrophages.
• validation of the manipulation of the inflammatory pathways identified in in vivo mouse models.

Project 2: Investigate the metabolic control of inflammation and infection induced by Gram-negative bacteria (Prof. Dr. Hamid Kashkar).

This interdisciplinary project is based on our previous observation indicating that cells facing Gram-negative bacteria change their mitochondrial bioenergetics and eventually release mitochondrial factors into the cytoplasm that activate distinct cellular inflammatory signaling. We could show that this metabolic switch does not interfere with cellular viability, but decisively controls pathogen propagation and host-mediated inflammatory signaling (Andree et al., EMBO J 2014 and unpublished data). Additional data showed that bacterial biosynthesis of lipopolysaccharide (LPS), in particular, the long-chain O-antigen polysaccharide (O-antigen) moiety of LPS is important for intracellular propagation of Gram-negative bacteria (Gunther et al., Nat Microbiol 2020). The central objective of this IP is to explore the metabolic crosstalk between host (animal and plant cells) and Pseudomonas aeruginosa. P. aeruginosa is a common Gram-negative aerobic- and facultative anaerobic-bacterium which is a ubiquitously distributed opportunistic pathogen that inhabits animal-, human-, and plant-host environments. This ubiquity is attributed to its very versatile energy metabolism as P. aeruginosa has a highly branched respiratory chain terminated by multiple terminal oxidases and denitrification enzymes. i-HEAD provides a perfect scientific environment to address such overarching questions controlling immunity and infection by P. aeruginosa in both animal and plant hosts. We strive to:

• monitor the metabolic programs of host and microbe during the course of infection.
• genetically disconnect this metabolic crosstalk by targeting distinct metabolic pathways and will examine host-bacteria interaction.