Franco 2020 bioRxiv
Franco JLM, Genoula M, Corral D, Duette G, Ferreyra M, Maio M, Dolotowicz MB, Aparicio-Trejo OE, Patiño-Martínez E, Fuentes F, Soldan V, Moraña EJ, Palmero D, Ostrowski M, Schierloh P, Sánchez-Torres C, Hernández-Pando R, Pedraza-Chaverri J, Rombouts Y, Layre E, Hudrisier D, Vérollet C, Neyrolles O, Sasiain MC, Lugo-Villarino G, Balboa L (2020) Host-derived lipids from tuberculous pleurisy impair macrophage microbicidal-associated metabolic activity. bioRxiv doi: https://doi.org/10.1101/2020.03.23.001818 . |
Franco JLM, Genoula M, Corral D, Duette G, Ferreyra M, Maio M, Dolotowicz MB, Aparicio-Trejo OE, Patino-Martinez E, Fuentes F, Soldan V, Morana EJ, Palmero D, Ostrowski M, Schierloh P, Sanchez-Torres C, Hernandez-Pando R, Pedraza-Chaverri J, Rombouts Y, Layre E, Hudrisier D, Verollet C, Neyrolles O, Sasiain MC, Lugo-Villarino G, Balboa L (2020) bioRxiv
Abstract: Mycobacterium tuberculosis (Mtb) regulates the macrophage metabolic state to thrive in the host. Yet, the responsible mechanisms remain elusive. Macrophage activation towards the microbicidal (M1) program depends on the HIF-1 α-mediated metabolic shift from oxidative phosphorylation towards glycolysis. Here, we asked whether a tuberculosis (TB) microenvironment changes the M1 macrophage metabolic state. We exposed M1 macrophages to the acellular fraction of tuberculous pleural effusions (TB-PE), and found lower glycolytic activity, accompanied by elevated levels of oxidative phosphorylation and bacillary load, compared to controls. The host-derived lipid fraction of TB-PE drove these metabolic alterations. HIF-1α stabilization reverted the effect of TB-PE by restoring M1 metabolism. As a proof-of-concept, Mtb-infected mice with stabilized HIF-1α displayed lower bacillary loads and a pronounced M1-like metabolic profile in alveolar macrophages. Collectively, we demonstrate that host-derived lipids from a TB-associated microenvironment alter the M1 macrophage metabolic reprogramming by hampering HIF-1α functions, thereby impairing control of Mtb infection. • Keywords: Macrophages, Tuberculosis, Oxygen consumption, Aerobic glycolytic, HIF-1α, Pleural effusion • Bioblast editor: Plangger M • O2k-Network Lab: MX Mexico City Pedraza Chaverri J
Labels: MiParea: Respiration
Pathology: Infectious
Organism: Human Tissue;cell: Macrophage-derived Preparation: Intact cells
Coupling state: LEAK, ROUTINE
Pathway: N, S, CIV, ROX
HRR: Oxygraph-2k
2020-05