title: Broad defects in the energy metabolism of leukocytes underlie immunoparalysis in sepsis.
abstract: The acute phase of sepsis is characterized by a strong inflammatory reaction. At later stages in some patients, immunoparalysis may be encountered, which is associated with a poor outcome. By transcriptional and metabolic profiling of human patients with sepsis, we found that a shift from oxidative phosphorylation to aerobic glycolysis was an important component of initial activation of host defense. Blocking metabolic pathways with metformin diminished cytokine production and increased mortality in systemic fungal infection in mice. In contrast, in leukocytes rendered tolerant by exposure to lipopolysaccharide or after isolation from patients with sepsis and immunoparalysis, a generalized metabolic defect at the level of both glycolysis and oxidative metabolism was apparent, which was restored after recovery of the patients. Finally, the immunometabolic defects in humans were partially restored by therapy with recombinant interferon-γ, which suggested that metabolic processes might represent a therapeutic target in sepsis.
authors.affiliation: Department of Internal Medicine and Radboud Center for Infectious Diseases, Radboud University Medical Center, Nijmegen, the Netherlands.
authors.forename: Shih-Chin
authors.identifier: http://orcid.org/0000-0003-1251-8774
authors.initials: SC
authors.lastname: Cheng
authors.affiliation: Center of Experimental &Molecular Medicine, Division of Infectious Diseases, Amsterdam Medical Center, University of Amsterdam, Amsterdam, the Netherlands.
authors.forename: Brendon P
authors.initials: BP
authors.lastname: Scicluna
authors.affiliation: Department of Internal Medicine and Radboud Center for Infectious Diseases, Radboud University Medical Center, Nijmegen, the Netherlands.
authors.forename: Rob J W
authors.initials: RJ
authors.lastname: Arts
authors.affiliation: Department of Internal Medicine and Radboud Center for Infectious Diseases, Radboud University Medical Center, Nijmegen, the Netherlands.
authors.forename: Mark S
authors.initials: MS
authors.lastname: Gresnigt
authors.affiliation: Department of Internal Medicine and Radboud Center for Infectious Diseases, Radboud University Medical Center, Nijmegen, the Netherlands.
authors.forename: Ekta
authors.initials: E
authors.lastname: Lachmandas
authors.affiliation: 4th Department of Internal Medicine, University of Athens, Medical School, Athens, Greece.
authors.forename: Evangelos J
authors.identifier: http://orcid.org/0000-0003-4713-3911
authors.initials: EJ
authors.lastname: Giamarellos-Bourboulis
authors.affiliation: Department of Intensive Care and Radboud Center for Infectious Diseases, Radboud University Medical Center, Nijmegen, the Netherlands.
authors.forename: Matthijs
authors.initials: M
authors.lastname: Kox
authors.affiliation: Department of Biochemistry, Radboud Institute for Molecular Life Sciences, Nijmegen, the Netherlands.|Institute of Metabolism and Systems Research, University of Birmingham, Birmingham, UK.
authors.forename: Ganesh R
authors.initials: GR
authors.lastname: Manjeri
authors.affiliation: Department of Biochemistry, Radboud Institute for Molecular Life Sciences, Nijmegen, the Netherlands.
authors.forename: Jori A L
authors.initials: JA
authors.lastname: Wagenaars
authors.affiliation: Department of Intensive Care Medicine, University Medical Center Utrecht, Utrecht, the Netherlands.
authors.forename: Olaf L
authors.initials: OL
authors.lastname: Cremer
authors.affiliation: Department of Internal Medicine and Radboud Center for Infectious Diseases, Radboud University Medical Center, Nijmegen, the Netherlands.|Department of Intensive Care and Radboud Center for Infectious Diseases, Radboud University Medical Center, Nijmegen, the Netherlands.
authors.forename: Jenneke
authors.initials: J
authors.lastname: Leentjens
authors.affiliation: Center of Experimental &Molecular Medicine, Division of Infectious Diseases, Amsterdam Medical Center, University of Amsterdam, Amsterdam, the Netherlands.
authors.forename: Anne J
authors.initials: AJ
authors.lastname: van der Meer
authors.affiliation: Department of Internal Medicine and Radboud Center for Infectious Diseases, Radboud University Medical Center, Nijmegen, the Netherlands.
authors.forename: Frank L
authors.initials: FL
authors.lastname: van de Veerdonk
authors.affiliation: Department of Medical Microbiology, University Medical Center Utrecht, Utrecht, the Netherlands.|Julius Center for Health Sciences and Primary Care, University Medical Center Utrecht, Utrecht, the Netherlands.
authors.forename: Marc J
authors.initials: MJ
authors.lastname: Bonten
authors.affiliation: Department of Intensive Care Medicine Academic Medical Center, University of Amsterdam, Amsterdam, the Netherlands.
authors.forename: Marcus J
authors.initials: MJ
authors.lastname: Schultz
authors.affiliation: Department of Biochemistry, Radboud Institute for Molecular Life Sciences, Nijmegen, the Netherlands.
authors.forename: Peter H G M
authors.initials: PH
authors.lastname: Willems
authors.affiliation: Department of Intensive Care and Radboud Center for Infectious Diseases, Radboud University Medical Center, Nijmegen, the Netherlands.
authors.forename: Peter
authors.initials: P
authors.lastname: Pickkers
authors.affiliation: Department of Internal Medicine and Radboud Center for Infectious Diseases, Radboud University Medical Center, Nijmegen, the Netherlands.
authors.forename: Leo A B
authors.initials: LA
authors.lastname: Joosten
authors.affiliation: Center of Experimental &Molecular Medicine, Division of Infectious Diseases, Amsterdam Medical Center, University of Amsterdam, Amsterdam, the Netherlands.
authors.forename: Tom
authors.initials: T
authors.lastname: van der Poll
authors.affiliation: Department of Internal Medicine and Radboud Center for Infectious Diseases, Radboud University Medical Center, Nijmegen, the Netherlands.
authors.forename: Mihai G
authors.initials: MG
authors.lastname: Netea
mesh_terms: D000255:Adenosine Triphosphate / Q000378:metabolism; D000328:Adult; D000818:Animals; D000935:Antifungal Agents / Q000627:therapeutic use; D001228:Aspergillosis / Q000188:drug therapy / Q000276:immunology / Q000378:metabolism; D058365:Candidiasis, Invasive / Q000188:drug therapy / Q000276:immunology / Q000378:metabolism; D016207:Cytokines / Q000276:immunology*; D019446:Endotoxemia / Q000276:immunology* / Q000378:metabolism; D004734:Energy Metabolism / Q000276:immunology*; D004927:Escherichia coli Infections / Q000276:immunology / Q000378:metabolism; D005260:Female; D006019:Glycolysis; D006801:Humans; D007108:Immune Tolerance / Q000276:immunology*; D007113:Immunity, Innate / Q000276:immunology*; D015151:Immunoblotting; D007371:Interferon-gamma / Q000627:therapeutic use; D019344:Lactic Acid / Q000378:metabolism; D007962:Leukocytes / Q000276:immunology / Q000378:metabolism; D008070:Lipopolysaccharides / Q000276:immunology; D008264:Macrophages / Q000276:immunology* / Q000378:metabolism; D008297:Male; D051379:Mice; D008875:Middle Aged; D009000:Monocytes / Q000276:immunology* / Q000378:metabolism; D009243:NAD / Q000378:metabolism; D010085:Oxidative Phosphorylation; D010101:Oxygen Consumption; D011446:Prospective Studies; D018805:Sepsis / Q000188:drug therapy / Q000276:immunology* / Q000378:metabolism; D059467:Transcriptome; D055815:Young Adult
chemical_list: D000935:Antifungal Agents; D016207:Cytokines; D008070:Lipopolysaccharides; D009243:NAD; D019344:Lactic Acid; D007371:Interferon-gamma; D000255:Adenosine Triphosphate