Metabolic reprogramming of Salmonella infected macrophages and its modulation by iron availability and the mTOR pathway

Authors:

Julia Telser1,2,#, Chiara Volani1,3,#, Richard Hilbe1,2, Markus Seifert1,2, Natascha Brigo1, Giuseppe Paglia4 and Günter Weiss1,2

doi: 10.15698/mic2019.12.700
Volume 6, pp. 531 to 543, published 14/11/2019.

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Affiliations:

1 Department of Internal Medicine II, Medical University of Innsbruck, Austria.

2 Christian Doppler Laboratory for Iron Metabolism and Anemia Research, Medical University of Innsbruck, Austria.

3 EURAC Research, Institute for Biomedicine, Bolzano/Bozen, Italy.

4 School of Medicine and Surgery, Univerity of Milano-Bicocca.

# Equal contribution.

Keywords: 

macrophage, Salmonella, Krebs cycle, iron, mTOR, glycolysis.

Corresponding Author(s):

Guenter Weiss, MD, , Department of Internal Medicine II, Infectious Diseases, Immunology, Pneumology and Rheumatology, Medical University Innsbruck, Anichstr. 35, A-6020 Innsbruck, Austria; Phone: +43-512-504-23251; Fax: +43-512-504-23317; guenter.weiss@i-med.ac.at

Conflict of interest statement:

The authors declare to have no conflict of interest.

Please cite this article as:

Julia Telser, Chiara Volani, Richard Hilbe, Markus Seifert, Na-tascha Brigo, Giuseppe Paglia and Günter Weiss (2019). Metabolic reprogramming of Salmonella infected macro-phages and its modulation by iron availability and the mTOR pathway. Microbial Cell 5(12): 531-543. doi: 10.15698/mic2019.12.700

© 2019 Telser et al. This is an open-access article released under the terms of the Creative Commons Attribution (CC BY) license, which allows the unrestricted use, distribution, and reproduc-tion in any medium, provided the original author and source are acknowledged.

Abstract:

Iron is an essential nutrient for immune cells and microbes, therefore the control of its homeostasis plays a decisive role for infections. Moreover, iron affects metabolic pathways by modulating the translational expression of the key tricarboxylic acid cycle (TCA) enzyme mitochondrial aconitase and the energy formation by mitochondria. Recent data provide evidence for metabolic re-programming of immune cells including macrophages during infection which is centrally controlled by mTOR. We herein studied the effects of iron perturbations on metabolic profiles in macrophages upon infection with the intracellular bacterium Salmonella enterica serovar Typhimurium and analysed for a link to the mTOR pathway. Infection of the murine macrophage cell line RAW264.7 with Salmonella resulted in the induction of mTOR activity, anaerobic glycolysis and inhibition of the TCA activity as reflected by reduced pyruvate and increased lactate levels. In contrast, iron supplementation to macrophages not only affected the mRNA expression of TCA and glycolytic enzymes but also resulted in metabolic reprogramming with increased pyruvate accumulation and reduced lactate levels apart from modulating the concentrations of several other metabolites. While mTOR slightly affected cellular iron homeostasis in infected macrophages, mTOR inhibition by rapamycin resulted in a significant growth promotion of bacteria. Importantly, iron further increased bacterial numbers in rapamycin treated macrophages, however, the metabolic profiles induced by iron in the presence or absence of mTOR activity differed in several aspects. Our data indicate, that iron not only serves as a bacterial nutrient but also acts as a metabolic modulator of the TCA cycle, partly reversing the Warburg effect and resulting in a pathogen friendly nutritional environment.