Franco 2020 bioRxiv
| Franco JLM, Genoula M, Corral D, Duette G, Ferreyra M, Maio M, Dolotowicz MB, Aparicio-Trejo OE, PatiΓ±o-MartΓnez E, Fuentes F, Soldan V, MoraΓ±a EJ, Palmero D, Ostrowski M, Schierloh P, SΓ‘nchez-Torres C, HernΓ‘ndez-Pando R, Pedraza-Chaverri J, Rombouts Y, Layre E, Hudrisier D, VΓ©rollet 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 Ξ±-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-1Ξ± stabilization reverted the effect of TB-PE by restoring M1 metabolism. As a proof-of-concept, Mtb-infected mice with stabilized HIF-1Ξ± 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-1Ξ± functions, thereby impairing control of Mtb infection. β’ Keywords: Macrophages, Tuberculosis, Oxygen consumption, Aerobic glycolytic, HIF-1Ξ±, Pleural effusion β’ Bioblast editor: Plangger M
Labels: MiParea: Respiration
HRR: Oxygraph-2k
2020-05
