Rewiring cellular metabolism via the AKT/mTOR pathway contributes to host defence against Mycobacterium tuberculosis in human and murine cells.

Abstract:

: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.

journal_name

Eur J Immunol

authors

Lachmandas E,Beigier-Bompadre M,Cheng SC,Kumar V,van Laarhoven A,Wang X,Ammerdorffer A,Boutens L,de Jong D,Kanneganti TD,Gresnigt MS,Ottenhoff TH,Joosten LA,Stienstra R,Wijmenga C,Kaufmann SH,van Crevel R,Netea MG

doi

10.1002/eji.201546259

subject

Has Abstract

pub_date

2016-11-01 00:00:00

pages

2574-2586

issue

11

eissn

0014-2980

issn

1521-4141

journal_volume

46

pub_type

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