The Lipid Virulence Factors of <i>Mycobacterium tuberculosis </i>Exert Multilayered Control over Autophagy-Related Pathways in Infected Human Macrophages
Autophagy is an important innate immune defense mechanism that controls <i>Mycobacterium tuberculosis</i> (<i>Mtb</i>) growth inside macrophages. Autophagy machinery targets <i>Mtb</i>-containing phagosomes via xenophagy after damage to the phagosomal membrane due...
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MDPI AG
2020-03-01
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| Series: | Cells |
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| Online Access: | https://www.mdpi.com/2073-4409/9/3/666 |
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| author | Aïcha Bah Merlin Sanicas Jérôme Nigou Christophe Guilhot Catherine Astarie-Dequeker Isabelle Vergne |
| author_facet | Aïcha Bah Merlin Sanicas Jérôme Nigou Christophe Guilhot Catherine Astarie-Dequeker Isabelle Vergne |
| author_sort | Aïcha Bah |
| collection | DOAJ |
| description | Autophagy is an important innate immune defense mechanism that controls <i>Mycobacterium tuberculosis</i> (<i>Mtb</i>) growth inside macrophages. Autophagy machinery targets <i>Mtb</i>-containing phagosomes via xenophagy after damage to the phagosomal membrane due to the Type VII secretion system Esx-1 or via LC3-associated phagocytosis without phagosomal damage. Conversely, <i>Mtb</i> restricts autophagy-related pathways via the production of various bacterial protein factors. Although bacterial lipids are known to play strategic functions in <i>Mtb</i> pathogenesis, their role in autophagy manipulation remains largely unexplored. Here, we report that the lipid virulence factors sulfoglycolipids (SLs) and phthiocerol dimycocerosates (DIMs) control autophagy-related pathways through distinct mechanisms in human macrophages. Using knock-out and knock-in mutants of <i>Mtb</i> and <i>Mycobacterium </i><i>bovis</i> BCG (Bacille Calmette Guerin) and purified lipids, we found that (i) <i>Mtb</i> mutants with DIM and SL deficiencies promoted functional autophagy via an MyD88-dependent and phagosomal damage-independent pathway in human macrophages; (ii) SLs limited this pathway by acting as TLR2 antagonists; (iii) DIMs prevented phagosomal damage-independent autophagy while promoting Esx-1-dependent xenophagy; (iv) and DIMs, but not SLs, limited the acidification of LC3-positive <i>Mtb</i> compartments. In total, our study reveals an unexpected and intricate role for <i>Mtb</i><i> </i>lipid virulence factors in controlling autophagy-related pathways in human macrophages, thus providing further insight into the autophagy manipulation tactics deployed by intracellular bacterial pathogens. |
| first_indexed | 2024-03-12T09:48:37Z |
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| institution | Directory Open Access Journal |
| issn | 2073-4409 |
| language | English |
| last_indexed | 2024-03-12T09:48:37Z |
| publishDate | 2020-03-01 |
| publisher | MDPI AG |
| record_format | Article |
| series | Cells |
| spelling | doaj.art-e8dfc52f0e2d4bf0ad4919b7953cc41c2023-09-02T12:45:00ZengMDPI AGCells2073-44092020-03-019366610.3390/cells9030666cells9030666The Lipid Virulence Factors of <i>Mycobacterium tuberculosis </i>Exert Multilayered Control over Autophagy-Related Pathways in Infected Human MacrophagesAïcha Bah0Merlin Sanicas1Jérôme Nigou2Christophe Guilhot3Catherine Astarie-Dequeker4Isabelle Vergne5Institut de Pharmacologie et de Biologie Structurale, Université de Toulouse, CNRS, Université Paul Sabatier, 31077 Toulouse, FranceInstitut de Pharmacologie et de Biologie Structurale, Université de Toulouse, CNRS, Université Paul Sabatier, 31077 Toulouse, FranceInstitut de Pharmacologie et de Biologie Structurale, Université de Toulouse, CNRS, Université Paul Sabatier, 31077 Toulouse, FranceInstitut de Pharmacologie et de Biologie Structurale, Université de Toulouse, CNRS, Université Paul Sabatier, 31077 Toulouse, FranceInstitut de Pharmacologie et de Biologie Structurale, Université de Toulouse, CNRS, Université Paul Sabatier, 31077 Toulouse, FranceInstitut de Pharmacologie et de Biologie Structurale, Université de Toulouse, CNRS, Université Paul Sabatier, 31077 Toulouse, FranceAutophagy is an important innate immune defense mechanism that controls <i>Mycobacterium tuberculosis</i> (<i>Mtb</i>) growth inside macrophages. Autophagy machinery targets <i>Mtb</i>-containing phagosomes via xenophagy after damage to the phagosomal membrane due to the Type VII secretion system Esx-1 or via LC3-associated phagocytosis without phagosomal damage. Conversely, <i>Mtb</i> restricts autophagy-related pathways via the production of various bacterial protein factors. Although bacterial lipids are known to play strategic functions in <i>Mtb</i> pathogenesis, their role in autophagy manipulation remains largely unexplored. Here, we report that the lipid virulence factors sulfoglycolipids (SLs) and phthiocerol dimycocerosates (DIMs) control autophagy-related pathways through distinct mechanisms in human macrophages. Using knock-out and knock-in mutants of <i>Mtb</i> and <i>Mycobacterium </i><i>bovis</i> BCG (Bacille Calmette Guerin) and purified lipids, we found that (i) <i>Mtb</i> mutants with DIM and SL deficiencies promoted functional autophagy via an MyD88-dependent and phagosomal damage-independent pathway in human macrophages; (ii) SLs limited this pathway by acting as TLR2 antagonists; (iii) DIMs prevented phagosomal damage-independent autophagy while promoting Esx-1-dependent xenophagy; (iv) and DIMs, but not SLs, limited the acidification of LC3-positive <i>Mtb</i> compartments. In total, our study reveals an unexpected and intricate role for <i>Mtb</i><i> </i>lipid virulence factors in controlling autophagy-related pathways in human macrophages, thus providing further insight into the autophagy manipulation tactics deployed by intracellular bacterial pathogens.https://www.mdpi.com/2073-4409/9/3/666autophagymycobacteriumtuberculosislipidsmacrophagephagosomelysosomesinnate immunity |
| spellingShingle | Aïcha Bah Merlin Sanicas Jérôme Nigou Christophe Guilhot Catherine Astarie-Dequeker Isabelle Vergne The Lipid Virulence Factors of <i>Mycobacterium tuberculosis </i>Exert Multilayered Control over Autophagy-Related Pathways in Infected Human Macrophages Cells autophagy mycobacterium tuberculosis lipids macrophage phagosome lysosomes innate immunity |
| title | The Lipid Virulence Factors of <i>Mycobacterium tuberculosis </i>Exert Multilayered Control over Autophagy-Related Pathways in Infected Human Macrophages |
| title_full | The Lipid Virulence Factors of <i>Mycobacterium tuberculosis </i>Exert Multilayered Control over Autophagy-Related Pathways in Infected Human Macrophages |
| title_fullStr | The Lipid Virulence Factors of <i>Mycobacterium tuberculosis </i>Exert Multilayered Control over Autophagy-Related Pathways in Infected Human Macrophages |
| title_full_unstemmed | The Lipid Virulence Factors of <i>Mycobacterium tuberculosis </i>Exert Multilayered Control over Autophagy-Related Pathways in Infected Human Macrophages |
| title_short | The Lipid Virulence Factors of <i>Mycobacterium tuberculosis </i>Exert Multilayered Control over Autophagy-Related Pathways in Infected Human Macrophages |
| title_sort | lipid virulence factors of i mycobacterium tuberculosis i exert multilayered control over autophagy related pathways in infected human macrophages |
| topic | autophagy mycobacterium tuberculosis lipids macrophage phagosome lysosomes innate immunity |
| url | https://www.mdpi.com/2073-4409/9/3/666 |
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