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Immunometabolic circuits in sepsis: restoring host defense mechanisms

Projectomschrijving

Sepsis (bloedvergiftiging) treedt op als de afweer een infectie niet kan controleren. Sepsis leidt tot een verstoorde functie van witte bloedcellen. Deze cellen voorzien in hun energie door afbraak van glucose via glycolyse. Witte bloedcellen van sepsis patiënten vertonen een sterk geremde glycolyse en kunnen daardoor niet goed reageren op bacteriën. Het project beoogt bij patiënten en muizen met sepsis te onderzoeken hoe de energiehuishouding van witte bloedcellen veranderd is, en (bij muizen) wat het effect is van manipulatie van het glucose metabolisme in deze cellen op de afweer. De meest veelbelovende interventies zullen getest worden bij gezonde vrijwilligers in een model van ontsteking geïnduceerd door een gezuiverd bacterie bestanddeel. Indien blijkt dat een geremde glycolyse in witte bloedcellen inderdaad ten grondslag ligt aan de verstoorde afweer bij sepsis, dan biedt dit uitzicht op nieuwe mogelijkheden om de uitkomst van sepsis te verbeteren.

Producten

Titel: Hypoxia-inducible factor (HIF)1a in macrophages, but not in neutrophils, is important for host defense during K. pneumoniae-induced pneumosepsis
Auteur: N.A. Otto, J.W.J. van Heijst, A.F. de Vos and T. van der Poll
Titel: Metabolic redundancy in the regulation of cytokine production by human monocytes
Auteur: N.A. Otto, I. Ramirez-Moral, J.W.J. van Heijst, A.F. de Vos and T. van der Poll
Titel: Expression of the cellular energy sensor LKB1 is important for the local host defense during gram-negative pneumonia
Auteur: N.A. Otto, A.F. de Vos, J.W.J. van Heijst and T. van der Poll
Titel: Monocyte adherence influences the function and metabolic programming upon stimulation with lipopolysaccharide
Auteur: N.A. Otto, I. Ramirez-Moral, J.W.J. van Heijst, A.F. de Vos and T. van der Poll
Titel: Pyruvate dehydrogenase complex stimulation promotes immunometabolic homeostasis and sepsis survival
Auteur: McCall, Charles E., Zabalawi, Manal, Liu, Tiefu, Martin, Ayana, Long, David L., Buechler, Nancy L., Arts, Rob J. W., Netea, Mihai, Yoza, Barbara K., Stacpoole, Peter W., Vachharajani, Vidula
Magazine: Journal of Clinical Investigation
Titel: Endotoxin-induced immunotolerance is associated with loss of monocyte metabolic plasticity and reduction of oxidative burst
Auteur: Grondman, Inge, Arts, Rob J. W., Koch, Rebecca M., Leijte, Guus P., Gerretsen, Jelle, Bruse, Niklas, Kempkes, Rosalie W. M., ter Horst, Rob, Kox, Matthijs, Pickkers, Peter, Netea, Mihai G., Gresnigt, Mark S.
Magazine: Journal of Leukocyte Biology
Titel: An integrative genomics approach identifies novel pathways that influence candidaemia susceptibility
Auteur: Matzaraki, Vasiliki, Gresnigt, Mark S., Jaeger, Martin, Ricaño-Ponce, Isis, Johnson, Melissa D., Oosting, Marije, Franke, Lude, Withoff, Sebo, Perfect, John R., Joosten, Leo A. B., Kullberg, Bart Jan, van de Veerdonk, Frank L., Jonkers, Iris, Li, Yang, Wijmenga, Cisca, Netea, Mihai G., Kumar, Vinod
Magazine: PLoS ONE
Titel: The Itaconate Pathway Is a Central Regulatory Node Linking Innate Immune Tolerance and Trained Immunity
Auteur: Domínguez-Andrés, Jorge, Novakovic, Boris, Li, Yang, Scicluna, Brendon P., Gresnigt, Mark S., Arts, Rob J.W., Oosting, Marije, Moorlag, Simone J.C.F.M., Groh, Laszlo A., Zwaag, Jelle, Koch, Rebecca M., ter Horst, Rob, Joosten, Leo A.B., Wijmenga, Cisca, Michelucci, Alessandro, van der Poll, Tom, Kox, Matthijs, Pickkers, Peter, Kumar, Vinod, Stunnenberg, Henk, Netea, Mihai G.
Magazine: Cell Metabolism
Titel: An integrative genomics approach identifies novel pathways that influence candidaemia susceptibility
Auteur: Matzaraki, Vasiliki, Gresnigt, Mark S., Jaeger, Martin, Ricaño-Ponce, Isis, Johnson, Melissa D., Oosting, Marije, Franke, Lude, Withoff, Sebo, Perfect, John R., Joosten, Leo A. B., Kullberg, Bart Jan, van de Veerdonk, Frank L., Jonkers, Iris, Li, Yang, Wijmenga, Cisca, Netea, Mihai G., Kumar, Vinod
Magazine: Lancet Infectious Diseases
Titel: Cellular metabolism of myeloid cells in sepsis
Auteur: Arts RJ, Gresnigt MS, Joosten LA, Netea MG
Magazine: Journal of Leukocyte Biology
Titel: Towards precision medicine in sepsis: a position paper from the European Society of Clinical Microbiology and Infectious Diseases
Auteur: Rello, J., van Engelen, T.S.R., Alp, E., Calandra, T., Cattoir, V., Kern, W.V., Netea, M.G., Nseir, S., Opal, S.M., van de Veerdonk, F.L., Wilcox, M.H., Wiersinga, W.J.
Magazine: Clinical Microbiology and Infection
Titel: The immunopathology of sepsis and potential therapeutic targets
Auteur: van der Poll, Tom, van de Veerdonk, Frank L., Scicluna, Brendon P., Netea, Mihai G.
Magazine: Nature Reviews Immunology
Titel: Rewiring monocyte glucose metabolism via C-type lectin signaling protects against disseminated candidiasis
Auteur: Domínguez-Andrés, Jorge, Arts, Rob J. W., ter Horst, Rob, Gresnigt, Mark S., Smeekens, Sanne P., Ratter, Jacqueline M., Lachmandas, Ekta, Boutens, Lily, van de Veerdonk, Frank L., Joosten, Leo A. B., Notebaart, Richard A., Ardavín, Carlos, Netea, Mihai G.
Magazine: PLoS Pathogens
Titel: Treatment With Acetylsalicylic Acid Reverses Endotoxin Tolerance in Humans In Vivo
Auteur: Leijte, Guus P., Kiers, Dorien, van der Heijden, Wouter, Jansen, Aron, Gerretsen, Jelle, Boerrigter, Verin, Netea, Mihai G., Kox, Matthijs, Pickkers, Peter
Magazine: Critical Care Medicine
Titel: Broad defects in the energy metabolism of leukocytes underlie immunoparalysis in sepsis
Auteur: Cheng, Shih-Chin, Scicluna, Brendon P, Arts, Rob J W, Gresnigt, Mark S, Lachmandas, Ekta, Giamarellos-Bourboulis, Evangelos J, Kox, Matthijs, Manjeri, Ganesh R, Wagenaars, Jori A L, Cremer, Olaf L, Leentjens, Jenneke, van der Meer, Anne J, van de Veerdonk, Frank L, Bonten, Marc J, Schultz, Marcus J, Willems, Peter H G M, Pickkers, Peter, Joosten, Leo A B, van der Poll, Tom, Netea, Mihai G
Magazine: Nature Immunology
Titel: Functional Annotation of Genetic Loci Associated With Sepsis Prioritizes Immune and Endothelial Cell Pathways
Auteur: Le, Kieu T. T., Matzaraki, Vasiliki, Netea, Mihai G., Wijmenga, Cisca, Moser, Jill, Kumar, Vinod
Magazine: Frontiers in Immunology
Titel: Current gaps in sepsis immunology: new opportunities for translational research
Auteur: Rubio, Ignacio, Osuchowski, Marcin F, Shankar-Hari, Manu, Skirecki, Tomasz, Winkler, Martin Sebastian, Lachmann, Gunnar, La Rosée, Paul, Monneret, Guillaume, Venet, Fabienne, Bauer, Michael, Brunkhorst, Frank M, Kox, Matthijs, Cavaillon, Jean-Marc, Uhle, Florian, Weigand, Markus A, Flohé, Stefanie B, Wiersinga, W Joost, Martin-Fernandez, Marta, Almansa, Raquel, Martin-Loeches, Ignacio, Torres, Antoni, Giamarellos-Bourboulis, Evangelos J, Girardis, Massimo, Cossarizza, Andrea, Netea, Mihai G, v
Magazine: Lancet Infectious Diseases

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Samenvatting van de aanvraag

Problem definition: Sepsis is a syndrome that arises when the body’s response to infection injures its own tissues. Sepsis represents a major health burden. In the US the number of sepsis cases exceeds one million per year and was recently reported to be rising by 13% annually. The case fatality rate of sepsis remains high at 15-30%. Until recently, sepsis was considered to result from an excessive inflammatory reaction generated in response to overwhelming infection. However, all clinical trials based on this assumption, testing the efficacy of anti-inflammatory agents, have failed. New insights indicate that sepsis causes a suppression of immune responses, a state referred to as “immunoparalysis”, which is now considered to be a major factor in sepsis lethality. This paradigm shift has pointed to completely new therapeutic leads for sepsis, focusing on immune stimulation rather than on inhibition of inflammation. The molecular mechanisms underlying immunoparalysis are largely unknown. Hypothesis: The applicants recently obtained novel molecular evidence for a significant shift in cell metabolism in patients with sepsis. Specifically, the transcriptome of leukocytes harvested from 50 patients with sepsis showed a common gene signature suggestive of a decrease in glycolytic cellular metabolism, with a concurrent increase in oxidative phosphorylation. Our completely new finding links with recent reports that cells with a proinflammatory phenotype metabolize pyruvate predominantly to lactate through a process called “aerobic glycolysis”, whereas cells with an immunotolerant phenotype preferentially use oxidative phosphorylation to metabolize glucose. Manipulation of cellular glucose metabolism in vitro strongly impacts on the inflammatory properties of the cells, pointing to a functional link between cell metabolism and inflammation. Together these data brought us to a groundbreaking concept concerning immunoparalysis in sepsis, namely that sepsis-associated immune suppression is caused by a shift in cellular metabolism from aerobic glycolysis to oxidative phosphorylation. Objectives: We seek to determine whether alterations in cellular metabolism in monocytes and macrophages, and in particular a defect in the capacity to mount aerobic glycolysis, drive immune suppression in patients with severe sepsis, and if so, whether this metabolic defect can be used as a specific therapeutic target in sepsis. Our major objectives are: (1) To assess the balance between glycolysis and oxidative metabolism, and the regulation thereof, in monocytes and macrophages during sepsis; (2) To determine the role of immunometabolic circuits for the functional phenotype of monocytes and macrophages in sepsis; (3) To study the effect of interventions aimed at reprogramming these metabolic alterations on immune suppression during sepsis. Approach: (1) We will investigate the balance between glycolysis and oxidative phosphorylation in monocytes and macrophages stimulated with sepsis pathogens in vitro, and in monocytes and/or macrophages harvested in mouse sepsis models, in the human endotoxemia model and from patients with sepsis. We will assess expression of glycolytic and oxidative phosphorylation genes, epigenetic patterns that might regulate their expression, the activation state of key factors (such as mTOR/HIF-1alpha, Akt, LKB1, AMPK, and PGC-1), intracellular metabolites, and the association of the metabolic state of the cell with its immune status. (2) We will determine the functional role of glycolysis and oxidative phosphorylation in host defense by genetic and pharmacological approaches to target key factors driving these processes in cell cultures and mouse sepsis models. In this latter part, we will use, a.o., mice with myeloid specific deletion of factors driving these two opposite metabolic pathways, i.e., mTOR, HIF-1alpha and LKB1. (3) We will test the effect of established and new compounds in their capacity to reverse immune suppression in monocytes by enhancing cellular glycolysis (or inhibiting oxidative phosphorylation). The most potent candidates will be tested in mouse sepsis models and the human endotoxemia model. Expected results, group strength and utilization: This project will provide entirely novel insight in the pathogenesis of sepsis, not only revealing how cellular glucose metabolism is altered in sepsis, but also providing clues to specific interventions able to reverse immunoparalysis. The applicants have individually contributed extensively to current understanding of sepsis pathogenesis and have published in top journals about this topic. This grant brings together their complementary expertise in a synergistic collaboration that allows them to build a strong consortium moving sepsis research in the Netherlands to a top international level. Both applicants are infectious disease physicians, permitting swift translation of basic findings into clinical applications.

Onderwerpen

Kenmerken

Projectnummer:
91214016
Looptijd: 100%
Looptijd: 100 %
2015
2020
Onderdeel van programma:
Gerelateerde subsidieronde:
Projectleider en penvoerder:
Prof. dr. T. van der Poll
Verantwoordelijke organisatie:
Amsterdam UMC - locatie AMC