De novo synthesized polyunsaturated fatty acids operate as both host immunomodulators and nutrients for Mycobacterium tuberculosis
- Institut Pasteur, France
- Institut de Pharmacologie et de Biologie Structurale (IPBS), CNRS UMR5089, France
- IFR 150, INSERM, France
Abstract
Successful control of Mycobacterium tuberculosis (Mtb) infection by macrophages relies on immunometabolic reprogramming, where the role of fatty acids (FAs) remains poorly understood. Recent studies unraveled Mtb's capacity to acquire saturated and monounsaturated FAs via the Mce1 importer. However upon activation, macrophages produce polyunsaturated FAs (PUFAs), mammal-specific FAs mediating the generation of immunomodulatory eicosanoids. Here, we asked how Mtb modulates de novo synthesis of PUFAs in primary mouse macrophages and whether this benefits host or pathogen. Quantitative lipidomics revealed that Mtb infection selectively activates the biosynthesis of w6 PUFAs upstream of the eicosanoid precursor arachidonic acid (AA), via transcriptional activation of Fads2. Inhibiting FADS2 in infected macrophages impaired their inflammatory and antimicrobial responses but had no effect on Mtb growth in mice. Using a click-chemistry approach, we found that Mtb efficiently imports w6 PUFAs via Mce1 in axenic culture, including AA. Further, Mtb preferentially internalized AA over all other FAs within infected macrophages, by mechanisms partially depending on Mce1 and supporting intracellular persistence. Notably, IFNγ repressed de novo synthesis of AA by infected mouse macrophages and restricted AA import by intracellular Mtb. Together, these findings identify AA as a major FA substrate for intracellular Mtb, whose mobilization by innate immune responses is opportunistically hijacked by the pathogen and downregulated by IFNγ.
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All data analysed during this study are included in the manuscript and supporting files.
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The authors declare that there was no external funding for this work.
Ethics
Animal experimentation: All animal experiments were performed in agreement with European and French guidelines (Directive 86/609/CEE and Decree 87- 848 of 19 October 1987). The study received the approval by the Institut Pasteur Safety Committee (Protocol 11.245) and the ethical approval by the local ethical committee "Comité d'Ethique en Experimentation Animale N{degree sign} 89 (CETEA)" (CETEA 200037 / APAFiS #27688).
Copyright
© 2021, Laval et al.
This article is distributed under the terms of the Creative Commons Attribution License permitting unrestricted use and redistribution provided that the original author and source are credited.
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De novo synthesized polyunsaturated fatty acids operate as both host immunomodulators and nutrients for Mycobacterium tuberculosis
eLife 10:e71946.
https://doi.org/10.7554/eLife.71946
