Characterization of tissue hibernation in sepsis as an adaptive response optimizing energy preservation.

• Applicant: Professor Dr. Sebastian Weis
• Subject Area: Anaesthesiology ; Parasitology and Biology of Tropical Infectious Disease Pathogens
• Term: from 2019 to 2024
• Project identifier: Deutsche Forschungsgemeinschaft (DFG) - Project number 437189240

The severity of infectious diseases is driven, in one way or another, by the extent of tissue damage imposed directly by pathogens, i.e. toxins or indirectly by host molecules and cells involved in pathogen clearance, i.e. immunopathology. Depending on the extent of tissue damage, organ dysfunction might become apparent and local infection progress to sepsis, the most severe form of an infectious disease. Therefore, targeting mechanisms that prevent organ dysfunction and sustain organismal homeostasis could provide sepsis-specific treatment, decrease disease severity and enhance survival. However, thorough dissection of and clear therapeutic strategies to exploit these protective pathways in infections are lacking. We could recently provide experimental evidence that adaptation of the hepatic metabolism is a central component of disease tolerance, a defense strategy that acts independent of the number of pathogens to otherwise lethal bacterial sepsis. Tissue damage control mechanisms are required to support hepatic glucose production and sustain organismal glucose metabolism during the course of the disease. Interestingly, adaptation in sepsis might also lead to a hibernation-like state that is associated with diminished metabolic activity. This shares features with the physiological occurring hibernation state of animals, an adaptive response to survive periods with limited food and energy supply. The central hypothesis to be tested under this proposal is that hibernation-like regulation underlies septic organ failure and is transmitted via reversible phosphorylation aiming at optimizing energy homeostasis and enhancing survival. As such, targeting hibernation should provide a novel therapeutic approach to confer tissue damage control and disease tolerance in septic patients. With this proposal we aim to s: i) assess whether there is a conserved hibernation-like and arousal-like phenotype in severe systemic infections, ii) dissect the underlying transcriptional, posttranslational and metabolic phenotype and iii) investigate whether hibernation-like phenotype are beneficial or detrimental in sepsis.

• DFG Programme: Research Grants