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De novo synthesized polyunsaturated fatty acids operate as both host immunomodulators and nutrients for Mycobacterium tuberculosis.
Laval, Thomas; Pedró-Cos, Laura; Malaga, Wladimir; Guenin-Macé, Laure; Pawlik, Alexandre; Mayau, Véronique; Yahia-Cherbal, Hanane; Delos, Océane; Frigui, Wafa; Bertrand-Michel, Justine; Guilhot, Christophe; Demangel, Caroline.
Afiliación
  • Laval T; Immunobiology of Infection Unit, Institut Pasteur, INSERM U1224, Université de Paris, Paris, France.
  • Pedró-Cos L; Université de Paris, Sorbonne Paris Cité, Paris, France.
  • Malaga W; Immunobiology of Infection Unit, Institut Pasteur, INSERM U1224, Université de Paris, Paris, France.
  • Guenin-Macé L; Université de Paris, Sorbonne Paris Cité, Paris, France.
  • Pawlik A; Institut de Pharmacologie et de Biologie Structurale (IPBS), Université de Toulouse, CNRS-UPS UMR 5089, Toulouse, France.
  • Mayau V; Immunobiology of Infection Unit, Institut Pasteur, INSERM U1224, Université de Paris, Paris, France.
  • Yahia-Cherbal H; Integrated Mycobacterial Pathogenomics Unit, Institut Pasteur, CNRS UMR 3525, Université de Paris, Paris, France.
  • Delos O; Immunobiology of Infection Unit, Institut Pasteur, INSERM U1224, Université de Paris, Paris, France.
  • Frigui W; Université de Paris, Sorbonne Paris Cité, Paris, France.
  • Bertrand-Michel J; Immunoregulation Unit, Institut Pasteur, INSERM U122, Université de Paris, Paris, France.
  • Guilhot C; MetaboHUB-MetaToul, National Infrastructure of Metabolomics and Fluxomics, Toulouse, France.
  • Demangel C; I2MC, Université de Toulouse, INSERM, Université Toulouse III - Paul Sabatier (UPS), Toulouse, France.
Elife ; 102021 12 24.
Article en En | MEDLINE | ID: mdl-34951591
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.
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Texto completo: 1 Bases de datos: MEDLINE Asunto principal: Ácidos Grasos Insaturados / Factores Inmunológicos / Mycobacterium tuberculosis Tipo de estudio: Prognostic_studies Límite: Animals / Female / Humans / Male Idioma: En Revista: Elife Año: 2021 Tipo del documento: Article País de afiliación: Francia

Texto completo: 1 Bases de datos: MEDLINE Asunto principal: Ácidos Grasos Insaturados / Factores Inmunológicos / Mycobacterium tuberculosis Tipo de estudio: Prognostic_studies Límite: Animals / Female / Humans / Male Idioma: En Revista: Elife Año: 2021 Tipo del documento: Article País de afiliación: Francia