Rewiring cellular metabolism via the AKT/mTOR pathway contributes to host defence against Mycobacterium tuberculosis in human and murine cells.
Cells in homeostasis metabolize glucose mainly through the tricarboxylic acid cycle and oxidative phosphorylation, while activated cells switch their basal metabolism to aerobic glycolysis. In this study, we examined whether metabolic reprogramming toward aerobic glycolysis is important for the host response to Mycobacterium tuberculosis (Mtb). Through transcriptional and metabolite analysis we show that Mtb induces a switch in host cellular metabolism toward aerobic glycolysis in human peripheral blood mononuclear cells (PBMCs). The metabolic switch is TLR2 dependent but NOD2 independent, and is mediated in part through activation of the AKT-mTOR (mammalian target of rapamycin) pathway. We show that pharmacological inhibition of the AKT/mTOR pathway inhibits cellular responses to Mtb both in vitro in human PBMCs, and in vivo in a model of murine tuberculosis. Our findings reveal a novel regulatory layer of host responses to Mtb that will aid understanding of host susceptibility to Mtb, and which may be exploited for host-directed therapy.
Department of Internal Medicine, Radboud Center for Infectious Diseases, Radboud University Medical Center, Nijmegen, The Netherlands.
Ekta
E
Lachmandas
Department of Immunology, Max Planck Institute for Infection Biology, Berlin, Germany.
Macarena
M
Beigier-Bompadre
Department of Internal Medicine, Radboud Center for Infectious Diseases, Radboud University Medical Center, Nijmegen, The Netherlands.
Shih-Chin
SC
Cheng
UMC Groningen University of Groningen, Groningen, The Netherlands.
Vinod
V
Kumar
Department of Internal Medicine, Radboud Center for Infectious Diseases, Radboud University Medical Center, Nijmegen, The Netherlands.
Arjan
A
van Laarhoven
Department of Internal Medicine, Radboud Center for Infectious Diseases, Radboud University Medical Center, Nijmegen, The Netherlands.|College of Computer, Qinghai Normal University, Xining, China.
Xinhui
X
Wang
Department of Internal Medicine, Radboud Center for Infectious Diseases, Radboud University Medical Center, Nijmegen, The Netherlands.
Anne
A
Ammerdorffer
Department of Internal Medicine, Radboud Center for Infectious Diseases, Radboud University Medical Center, Nijmegen, The Netherlands.
Lily
L
Boutens
Department of Gastroenterology, Radboud University Medical Center, Nijmegen, The Netherlands.
Dirk
D
de Jong
Department of Immunology, St. Jude Children's Research Hospital, Memphis, TN, USA.
Thirumala-Devi
TD
Kanneganti
Department of Internal Medicine, Radboud Center for Infectious Diseases, Radboud University Medical Center, Nijmegen, The Netherlands.
Mark S
MS
Gresnigt
Department of Infectious Diseases, Leiden University Medical Centre, Leiden, The Netherlands.
Tom H M
TH
Ottenhoff
Department of Internal Medicine, Radboud Center for Infectious Diseases, Radboud University Medical Center, Nijmegen, The Netherlands.
Leo A B
LA
Joosten
Department of Internal Medicine, Radboud Center for Infectious Diseases, Radboud University Medical Center, Nijmegen, The Netherlands.
Rinke
R
Stienstra
UMC Groningen University of Groningen, Groningen, The Netherlands.
Cisca
C
Wijmenga
Department of Immunology, Max Planck Institute for Infection Biology, Berlin, Germany.
Stefan H E
SH
Kaufmann
Department of Internal Medicine, Radboud Center for Infectious Diseases, Radboud University Medical Center, Nijmegen, The Netherlands.
Reinout
R
van Crevel
Department of Internal Medicine, Radboud Center for Infectious Diseases, Radboud University Medical Center, Nijmegen, The Netherlands. mihai.netea@radboudumc.nl.
Mihai G
MG
Netea
D000818:Animals; D000900:Anti-Bacterial Agents / Q000494:pharmacology; D020869:Gene Expression Profiling; D005947:Glucose / Q000378:metabolism; D006019:Glycolysis / Q000235:genetics; D054884:Host-Pathogen Interactions; D006801:Humans; D007963:Leukocytes, Mononuclear / Q000276:immunology / Q000378:metabolism* / Q000382:microbiology; D051379:Mice; D009169:Mycobacterium tuberculosis / Q000276:immunology*; D010085:Oxidative Phosphorylation; D051057:Proto-Oncogene Proteins c-akt / Q000378:metabolism*; D015398:Signal Transduction / Q000187:drug effects; D020123:Sirolimus / Q000494:pharmacology; D058570:TOR Serine-Threonine Kinases / Q000235:genetics / Q000276:immunology / Q000378:metabolism*; D051195:Toll-Like Receptor 2 / Q000276:immunology; D014376:Tuberculosis / Q000276:immunology / Q000378:metabolism / Q000382:microbiology
D000900:Anti-Bacterial Agents; C495342:TLR2 protein, human; C493486:Tlr2 protein, mouse; D051195:Toll-Like Receptor 2; C546842:MTOR protein, human; C546843:mTOR protein, mouse; C494918:AKT1 protein, human; C514862:Akt1 protein, mouse; D051057:Proto-Oncogene Proteins c-akt; D058570:TOR Serine-Threonine Kinases; D005947:Glucose; D020123:Sirolimus
Glycolysis; Immunometabolism; Mycobacterium tuberculosis; TLR2; mTOR