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 fatty acids (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 ω6 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 host cells nor mice. Using a click-chemistry approach, we found that Mtb efficiently imports ω6 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.
Highlights
50 51 Mycobacterium tuberculosis (Mtb), the causative agent of human Tuberculosis (TB), caused 1.6 million deaths in 2017 and it is estimated that 23% of the world’s population has a latent TB infection
They suggest that fatty acids (FAs) production results from activation 135 of SREBP1, and that polyunsaturated FAs (PUFAs) biosynthesis blockade downstream of FADS1 is due to a transient, post136 transcriptional repression of LXR activity. 137 138 IFNγ shuts down the biosynthesis of all FAs in M. tuberculosis-infected macrophages 139 Macrophage ability to mount efficient anti-Mtb responses relies on their activation by the Th1 cell140 derived cytokine IFNγ, recently shown to limit host FA intake by intracellular Mtb (Knight et al, 141 2018)
The partial upregulation of the PUFA biosynthetic pathway that we observed in Mtb-infected macrophages is abrogated by cell exposure to IFNγ. These results indicated that IFNγ shuts down the biosynthesis of all FAs in Mtb-infected macrophages. 168 FADS2 inhibition impairs the effector functions of macrophages during M. tuberculosis infection Long chain PUFAs can be mobilized by hydrolysis of phospholipids to fuel the production of lipid mediators of inflammation (Dennis and Norris, 2015)
Summary
28 29 Successful control of Mycobacterium tuberculosis (Mtb) infection by macrophages relies on immunometabolic reprogramming, where the role of fatty acids (FAs) remains poorly understood. 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 6 PUFAs upstream of the eicosanoid precursor arachidonic acid (AA), via transcriptional activation of Fads. 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 6 PUFAs via Mce in axenic culture, including AA. Mtb preferentially internalized AA over all other FAs within infected macrophages, by mechanisms partially depending on Mce and supporting intracellular persistence. 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. 47 48
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