TANK_Sepsis · Targeting Amino acid uptake into NK cells to limit pathogenesis in sepsis

Sepsis is a global health challenge, accounting for around 20% of deaths worldwide. While sepsis is induced by uncontrolled dissemination of infection, significant contribution to disease pathogenesis is made by overwhelming production of proinflammatory mediators, a so-called “cytokine storm”. There is a pressing need for new target therapies to dampen this immunopathogenesis while still allowing bacterial clearance. Although Natural Killer (NK) cells are vital for host innate responses, they are important contributors to the tissue damage during bacterial sepsis, in particular, via production of excessive amounts of IFNg. Therefore, dampening NK cell IFNg production represents a promising tool for sepsis treatment. Recent studies from the host institution have shown that metabolic processes are essential for NK cell functions. In particular, certain amino acid transporters are key to support IFNg expression by NK cells. I thus hypothesize that limiting amino acid supply to NK cells will restrict production of IFNg, dampen the cytokine storm, and improve the course of bacterial sepsis. To prove this idea, I will combine my experience in mouse models of septic shock with host institution’s background on immunometabolism and bacterial infections. First, I will employ a powerful “metabolic toolbox” established at the supervisor’s lab to characterize metabolic phenotype of NK cells in bacterial sepsis. Next, I will use mice with genetic ablation of key amino acid transporters specifically in NK cells to study their role in “cytokine storm” during sepsis. Finally, I will test pharmacological compounds, able to limit amino acid availability, for their potential to prevent excessive inflammation during sepsis. At the end of the project, I will acquire key professional skills, including “metabolic toolbox” and bacterial infection model, that will benefit my further career, as well as characterize new potential therapeutic opportunity for treatment of sepsis.