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

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• 作者：Ekta Lachmandas ; Macarena Beigier-Bompadre ; Shih-Chin Cheng ; Vinod Kumar ; Arjan van Laarhoven ; Xinhui Wang ; Anne Ammerdorffer ; Lily Boutens ; Dirk de Jong ; Thirumala-Devi Kanneganti ; Mark S. Gresnigt ; Tom H.M. Ottenhoff ; Leo A.B. Joosten ; Rinke Stienstra ; Cisca Wijmenga ; Stefan H.E. Kaufmann ; Reinout van Crevel and Mihai G. Netea
• 刊名：European Journal of Immunology
• 出版年：2016
• 出版时间：November 2016
• 年：2016
• 卷：46
• 期：11
• 页码：2574-2586
• 全文大小：2997K
• ISSN：1521-4141

文摘

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.