Responsible for 1.5 million deaths a year, tuberculosis is still the most deadly infectious disease today. The virulence of the bacterium responsible for this disease, Mycobacterium tuberculosis, relies in particular on its ability to modulate the metabolic pathways of macrophages. An international consortium led by researchers from IPBS-Toulouse (CNRS, University Toulouse III-Paul Sabatier) and the University of Buenos Aires discovered that host-derived lipids generated during infection with M. tuberculosis alter the metabolic activity of macrophages, resulting in decreased resistance to infection. These results are published in the journal Cell Reports on December 29, 2020.
Despite the great progress achieved in the fight against tuberculosis (TB), caused by Mycobacterium tuberculosis, it remains one of the top ten causes of death worldwide. The success of M. tuberculosis as a major pathogen relies in large part on its ability to regulate the metabolic pathways of macrophages. Indeed, an emerging theme within the field of host-pathogen interactions is the study of how host metabolic pathways are regulated to support or direct functional changes during pathogenic processes.
In the context of an international collaboration (LIA #1167, IM-TB/HIV), a collaboration between the laboratory of Drs. MDC Sasiain and L. Balboa at the IMEX CONICET — Academia Nacional de la Medicina de Buenos Aires (Argentina) — and three teams at IPBS-Toulouse, revealed that host-derived lipids generated during TB infection impair the metabolic activity essential for the host defense against this pathogen. A critical aspect of the work presented in this study is the use of tuberculous pleural effusions (TB-PE) — human-derived biological fluid capable of mimicking the complex microenvironment of the lung cavity upon M. tuberculosis infection — to study the metabolic modulation favoring pathogen resilience in human macrophages. Thanks to this original approach, the researchers now show that host-derived lipids found in TB-PE alter the metabolic reprogramming of microbicidal macrophages by hampering the functional activity of HIF-1α, a critical transcription factor that mediates aerobic glycolysis — the glucose degradation pathway to generate energy. Consequently, an oxidative phosphorylation, a metabolic state typical of macrophages that participates in anti-inflammatory processes such as tissue repair, is established along with poor production of lactate, reactive oxygen species and IL-1ß rendering macrophages highly susceptible to M. tuberculosis intracellular growth. As a proof-of-concept, in vitro and in vivo pharmacological stabilization of HIF-1α reverts these effects leading to better control of the pathogen burden.
This work contributes to the establishment of the acellular fraction of TB-PE as a physiologically relevant tuberculous-milieu, demonstrating its capacity to shift macrophage metabolism to the advantage of the pathogen. Indeed, it is proposed that human macrophages committed towards a pro-inflammatory profile to control the infection can be metabolically reprogrammed by host-derived lipids generated during the M. tuberculosis infection. In addition, its use will be complementary to current models of TB investigation, providing better understanding of the complex interaction between the host immune response and the bacilli, and the tissue environment where it takes place.
Mitochondria (blue-green) in macrophages incubated with pleural effusions from tuberculosis patients have abnormal morphologies. Scanning electron microcopy image taken on the METi platform (Vanessa Soldan).
© Christel Vérollet and Mélanie Genoula.
This work was funded by the CNRS, the University Toulouse III-Paul Sabatier, the National Agency for Research on AIDS and Viral Hepatitis, the National Research Agency, the Foundation for Medical Research, the Argentinean National Agency of Promotion of Science and Technology and the Argentinean National Council of Scientific and Technical Investigations.
Host-derived lipids from tuberculous pleurisy impair macrophage microbicidal-associated metabolic activity.
Marin-Franco JL, Genoula M, Corral D, Duette G, Ferreyra M, Maio M, Dolotowicz B, Aparicio-Trejo OE, Patińo-Martinez E, Charton A, Metais A, Fuentes F, Soldan V, Morańa EJ, Palmero D, Ostrowski M, Schierloh P, Sanchez-Torres C, Hernandez-Pando R, Pedraza-Chaverri J, Rombouts Y, Hudrisier D, Layre E, Vérollet C, Neyrolles O, Sasiain MDC, Lugo-Villarino G and Balboa L. Cell Reports 2020 DOI: 10.1016/j.celrep.2020.108547
Read the press release (in French) here
Researchers IPBS: Geanncarlo Lugo-Villarino | Geanncarlo.Lugo@ipbs.fr | @GClugo | +33 (0)5 61 17 59 10
Christel Vérollet | Christel.Verollet@ipbs.fr | @ChrisVerollet | +33 (0)5 61 17 54 56
Press IPBS: Francoise Viala | firstname.lastname@example.org | +33 (0)5 61 17 52 59