Poster De Conférence Année : 2020

The lipid virulence factors of Mycobacterium tuberculosis exert multilayered control over autophagy-related pathways in infected human macrophages

Résumé

Autophagy is an important innate immune defense mechanism that controls Mycobacterium tuberculosis (Mtb) growth inside macrophages. Autophagy machinery targets Mtbcontaining 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, Mtb restricts autophagy-related pathways via the production of various bacterial protein factors. Although bacterial lipids are known to play strategic functions in Mtb pathogenesis, their role in autophagy manipulation remains largely unexplored. Here, we report that the lipid virulence factors sulfoglycolipids (SL) and phthiocerol dimycocerosates (DIM) control autophagy-related pathways through distinct mechanisms in human macrophages. Using knockout and knock-in mutants of Mtb and M.bovis BCG (Bacille Calmette Guerin) and purified lipids, we found that (i) Mtb mutant with DIM and SL deficiencies promotes functional autophagy via a MyD88-dependent and phagosomal damage-independent pathway in human macrophages; (ii) SL limit this pathway by acting as TLR2 antagonists; (iii) DIM prevent phagosomal damage-independent autophagy while promoting Esx-1-dependent xenophagy; (iv) and DIM, but not SL, limit the acidification of LC3-positive Mtb compartments. In total, our study reveals an unexpected and intricate role for Mtb 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.

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hal-03382295 , version 1 (18-10-2021)

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  • HAL Id : hal-03382295 , version 1

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Aïcha Bah, Merlin Sanicas, Jérôme Nigou, Christophe Guilhot, Catherine Astarie-Dequeker, et al.. The lipid virulence factors of Mycobacterium tuberculosis exert multilayered control over autophagy-related pathways in infected human macrophages. eSymposia Keystone, Oct 2020, Kerry, Ireland. ⟨hal-03382295⟩
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