Disturbed metabolic adaptation drives natural killer cell dysfunction in association with nosocomial infection during human sepsis

BACKGROUND: Patients with sepsis are highly susceptible to detrimental nosocomial infections. During bacterial infection, natural killer (NK) cells release Interferon (IFN) γ that drives the elimination of invading pathogens. Interleukin (IL) 12 in synergy with other cytokines increases sensing and uptake of nutrients by NK cells for metabolic adaptation required for induction of IFN-γ production. We hypothesised that inappropriate function of NK cells was associated with nosocomial infections during human sepsis and linked to altered metabolic adaptation. METHODS: We performed a longitudinal exploratory study on circulating human NK cells during sepsis and evaluated adaptation of nutrient sensing, activation of the metabolic hub mammalian target of rapamycin (mTOR) C1, and IFN-γ production upon exposure to Staphylococcus aureus as a model for an opportunistic pathogen in vitro. The involvement of cell-intrinsic and extrinsic pathways in NK cell function was addressed. FINDINGS: Expression of the IL-12 receptor (p < 0.001) and downstream production of IFN-γ (p < 0.01) after exposure to S. aureus were suppressed in NK cells for at least 14 days after sepsis diagnosis, particularly in patients who developed secondary infections (p < 0.01). Mechanistically, suppression of NK cells was independent from environmental cues but was cell-intrinsic and associated with impaired activation of mTORC1 and with reduced expression of nutrient transporters required for anabolic metabolism. Inhibition of AMP kinase (AMPK) restored mTORC1 activity (p < 0.01) and increased the production of IFN-γ (p < 0.01) in NK cells from septic patients. INTERPRETATION: Defective metabolic regulation is associated with persistent NK cell dysfunction during human sepsis and might represent a potential therapeutic target to improve immune competence and decrease the risk for nosocomial infections. FUNDING: The study was supported by the "Research and Training" program "ELAN" for medical students of the medical faculty of the University Duisburg-Essen.