Sepsis involves simultaneous hyperactivation of the immune system and immune paralysis, leading to both organ dysfunction and increased susceptibility to secondary infections. Acute activation of myeloid cells induced itaconate synthesis, which subsequently mediated innate immune tolerance in human monocytes. In contrast, induction of trained immunity by b-glucan counteracted tolerance induced in a model of human endotoxemia by inhibiting the expression of immune-responsive gene 1 (IRG1), the enzyme that controls itaconate synthesis. b-Glucan also increased the expression of succinate dehydrogenase (SDH), contributing to the integrity of the TCA cycle and leading to an enhanced innate immune response after secondary stimulation. The role of itaconate was further validated by IRG1 and SDH polymorphisms that modulate induction of tolerance and trained immunity in human monocytes. These data demonstrate the importance of the IRG1-itaconate-SDH axis in the development of immune tolerance and training and highlight the potential of b-glucaninduced trained immunity to revert immunoparalysis.

a b s t r a c t a r t i c l e i n f oPurpose: While most influenza patients have a self-limited respiratory illness, 5-10% of hospitalized patients develop severe disease requiring ICU admission. The aim of this study was to identify influenza-specific factors associated with ICU admission and mortality. Furthermore, influenza-specific pulmonary bacterial, fungal and viral co-infections were investigated. Methods: 199 influenza patients, admitted to two academic hospitals in the Netherlands between 01-10-2015 and 01-04-2016 were investigated of which 45/199 were admitted to the ICU. Results: A history of Obstructive/Central Sleep Apnea Syndrome, myocardial infarction, dyspnea, influenza type A, BMI N 30, the development of renal failure and bacterial and fungal co-infections, were observed more frequently in patients who were admitted to the ICU, compared with patients at the normal ward. Co-infections were evident in 55.6% of ICU-admitted patients, compared with 20.1% of patients at the normal ward, mainly caused by Staphylococcus aureus, Streptococcus pneumoniae, and Aspergillus fumigatus. Non-survivors suffered from diabetes mellitus and (pre-existent) renal failure more often. Conclusions: The current study indicates that a history of OSAS/CSAS, myocardial infarction and BMI N 30 might be related to ICU admission in influenza patients. Second, ICU patients develop more pulmonary co-infections. Last, (pre-existent) renal failure and diabetes mellitus are more often observed in non-survivors.

IFN-γ partially reverses immunoparalysis in vivo in humans. These results suggest that IFN-γ is a promising treatment option to reverse sepsis-induced immunoparalysis.

Sickness behavior in humans is characterized by low mood and fatigue, which have been suggested to reflect changes in motivation involving reorganization of priorities. However, it is unclear which specific processes underlying motivation are altered. We tested whether bacterial endotoxin E. coli lipopolysaccharide (LPS) affected two dissociable constructs of motivational behavior, ie, effort and reward sensitivity. After familiarization with 5 effort levels, participants made a series of accept/reject decisions on whether the stake offered (1, 4, 8, 12, or 15 apples) was ‘worth the effort’ (10%, 27.5%, 45%, 62.5%, and 80% of maximal voluntary contraction in a hand-held dynamometer). Effort and reward levels were parametrically modulated to dissociate their influence on choice. Overall, 29 healthy young males were administered LPS (2 ng/kg; n=14) or placebo (0.9% saline; n=15). The effort-stake task, and self-reported depression and fatigue were assessed prior to LPS/placebo injection, 2 and 5 h post injection. Cytokines and sickness symptoms were assessed hourly till 8 h after LPS injection. LPS transiently increased interleukin-6 and tumor necrosis factor-α, sickness symptoms, body temperature and self-reported fatigue, and depression post injection relative to baseline and placebo. These changes were accompanied by LPS-induced decreases in acceptance rates of high-effort options, without significantly affecting reward sensitivity 2 h post injection, which were partially recovered 5 h post injection. We suggest that LPS-induced changes in motivation may be due to alterations to mesolimbic dopamine. Our behavioral paradigm could be used to further investigate effects of inflammation on motivational behavior in psychiatric and chronic illnesses.

Secondary infections are a major complication of sepsis and associated with a compromised immune state, called sepsis-induced immunoparalysis. Molecular mechanisms causing immunoparalysis remain unclear; however, changes in cellular metabolism of leukocytes have been linked to immunoparalysis. We investigated the relation of metabolic changes to antimicrobial monocyte functions in endotoxin-induced immunotolerance, as a model for sepsis-induced immunoparalysis. In this study, immunotolerance was induced in healthy males by intravenous endotoxin (2 ng/kg, derived from Escherichia coli O:113) administration. Before and after induction of immunotolerance, circulating CD14 + monocytes were isolated and assessed for antimicrobial functions, including cytokine production, oxidative burst, and microbial (Candida albicans) killing capacity, as well metabolic responses to ex vivo stimulation. Next, the effects of altered cellular metabolism on monocyte functions were validated in vitro. Ex vivo lipopolysaccharide stimulation induced an extensive rewiring of metabolism in naive monocytes. In contrast, endotoxin-induced immunotolerant monocytes showed no metabolic plasticity, as they were unable to adapt their metabolism or mount cytokine and oxidative responses. Validation experiments showed that modulation of metabolic pathways, affected by immunotolerance, influenced monocyte cytokine production, oxidative burst, and microbial (C. albicans) killing in naive monocytes. Collectively, these data demonstrate that immunotolerant monocytes are characterized by a loss of metabolic plasticity and these metabolic defects impact antimicrobial monocyte immune functions. Further, these findings support that the changed cellular metabolism of immunotolerant monocytes might reveal novel therapeutic targets to reverse sepsis-induced immunoparalysis. K E Y W O R D Sendotoxemia, endotoxin tolerance, immunometabolism, immunoparalysis, monocytes, sepsis Abbreviations: 2DG, 2-deoxy-D-glucose; 6AN, 6-aminonicotinamide; AUC, area under the curve; BPTES bis-2-(5-phenylacetamido-1,3,4-, bis-2-(5-phenylacetamido-1