Portal de Periódicos da CAPES

Host-Derived Lipids from Tuberculous Pleurisy Impair Macrophage Microbicidal-Associated Metabolic Activity

2020; RELX Group (Netherlands); Linguagem: Inglês

10.2139/ssrn.3553403

1556-5068

José Luis Marín Franco, Melanie Genoula, Dan Corral, Gabriel Duette, Malena Ferreyra, Mariano Maio, María Belén Dolotowicz, Omar Emiliano Aparicio‐Trejo, Eduardo Patiño‐Martínez, Federico Fuentes, Vanessa Soldan, Eduardo José Moraña, Domingo Palmero, Matías Ostrowski, Pablo Schierloh, Carmen Sánchez‐Torres, Rogelio Hernández‐Pando, José Pedraza‐Chaverrí, Yoann Rombouts, Emilie Layre, Denis Hudrisier, Christel Vérollet, Olivier Neyrolles, Marı́a del Carmen Sasiain, Geanncarlo Lugo‐Villarino, Luciana Balboa,

Tuberculosis Research and Epidemiology

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-1α-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.