The pleural effusions from TB patients alter the metabolic reprogramming of human macrophages by targeting HIF-1α activity

JOSÉ LUIS MARÍN FRANCO; MELANIE GENOULA; DAN CORRAL; MARIANO MAIO; MARÍA BELÉN DOLOTOWICZ; MALENA FERREYRA; FEDERICO FUENTES; EDUARDO JOSÉ MORAÑA; DOMINGO PALMERO; OLIVIER NEYROLLES; PABLO SCHIERLOH; MARÍA DEL CARMEN SASIAIN; GEANNCARLO LUGO-VILLARINO; LUCIANA BALBOA

Santa Fe, New Mexico

Simposio; Tuberculosis: Immunity and Immune Evasion; 2020

Keystone Symposia, fundación Bill & Melinda Gates

The success of Mycobacterium tuberculosis (Mtb) as the etiological agent of tuberculosis (TB) derives from the adaptation to the intracellular macrophages. Macrophage activation towards the pro-inflammatory and microbicidal (M1) program is accompanied by a metabolic shift towards glycolysis and away from oxidative phosphorylation (OXPHOS), a switch that is governed by the HIF-1α transcription factor. Here, we asked whether the microenvironment generated during Mtb infection leads changes in the metabolic pathways of M1 macrophages and impairment of microbicidal activity. Our approach was to activate M1 human macrophages using IFN-γ/LPS in the presence of the acellular fraction of tuberculous pleural effusions (TB-PE). We found that the release of lactate, the final glycolysis product, augmented in M1 macrophages, is reduced in the presence of TB-PE compared to cells exposed to pleural effusions from other etiologies. Additionally, these cells displayed an increased OXPHOS activity and a more tubular mitochondrial morphology compared to untreated M1 macrophages. TB-PE also promoted reduced HIF-1α and glycolytic genes expression levels, and lower pro-inflammatory functions in M1 macrophages, as well as a poor capacity to control the bacillary load. Strikingly, HIF-1α stabilization could revert the effect of TB-PE, restoring the M1 metabolism as well as the pro-inflammatory functions. As proof-of-concept, Mtb-infected mice treated with DMOG displayed lower bacillary loads and a pronounced M1-like metabolic profile in alveolar macrophages. In conclusion, we demonstrate that a TB-associated microenvironment alters the metabolic reprogramming of M1 macrophages through hampering HIF-1α functions, resulting in an impaired ability to control Mtb infection