Genetically diverse Mycobacterium tuberculosis isolates manipulate inflammasome activation and IL-1β secretion independently of macrophage metabolic rewiring

Ana Isabel Fernandes; Alexandre Jorge Pinto; Diogo Silvério; Ulrike Zedler; Carolina Ferreira; Iola F Duarte; Ricardo Silvestre; Anca Dorhoi; Margarida Saraiva

doi:10.1093/infdis/jiae583

Genetically diverse Mycobacterium tuberculosis isolates manipulate inflammasome activation and IL-1β secretion independently of macrophage metabolic rewiring

J Infect Dis. 2024 Nov 21:jiae583. doi: 10.1093/infdis/jiae583. Online ahead of print.

Authors

Ana Isabel Fernandes^{1

2}, Alexandre Jorge Pinto¹, Diogo Silvério^{1

2}, Ulrike Zedler³, Carolina Ferreira^{4

5}, Iola F Duarte⁶, Ricardo Silvestre^{4

5}, Anca Dorhoi^{3

7}, Margarida Saraiva^{1

8}

Affiliations

¹ Instituto de Investigação e Inovação em Saúde (i3S), Universidade do Porto, Porto, Portugal.
² Doctoral Program in Molecular and Cell Biology, Instituto de Ciências Biomédicas Abel Salazar (ICBAS), Universidade do Porto, Porto, Portugal.
³ Institute of Immunology, Friedrich-Loeffler-Institut (FLI), Greifswald-Insel Riems, Germany.
⁴ Life and Health Sciences, Research Institute (ICVS), School of Medicine, University of Minho, Braga, Portugal.
⁵ ICVS/3B's-PT Government Associate Laboratory, Braga, Portugal.
⁶ CICECO - Aveiro Institute of Materials, Department of Chemistry, University of Aveiro, Aveiro, Portugal.
⁷ Faculty of Mathematics and Natural Sciences, University of Greifswald, Greifswald, Germany.
⁸ IBMC - Instituto de Biologia Molecular e Celular, University of Porto, Porto, Portugal.

PMID: 39570738
DOI: 10.1093/infdis/jiae583

Abstract

The diversity of Mycobacterium tuberculosis (Mtb) impacts the outcome of tuberculosis. We previously showed that Mtb isolates obtained from patients with severe disease induced low inflammasome activation and IL-1β production by infected macrophages. Here we questioned whether this differential modulation of macrophages by Mtb isolates depended on distinct metabolic reprogramming. We found that the macrophage metabolic landscape was similar regardless of the infecting Mtb isolate. Paralleling single-TLR activated macrophages, glycolysis inhibition during infection impaired IL-1β secretion. However, departing from TLR based models, in infected macrophages, IL-1β secretion was independent of mitochondrial metabolic changes and HIF-1α. Additionally, we found an unappreciated impact of a host metabolic inhibitor on the pathogen, and show that inflammasome activation and IL-1β production by macrophages require metabolically active bacteria. Our study highlights the potential confounding effect of host metabolic inhibitors on the pathogen and uncouples Mtb-inflammasome modulation from the host metabolic reprogramming.

Keywords: Mycobacterium tuberculosis; immunometabolism; inflammasome; macrophage.

Plain language summary

Mycobacterium tuberculosis (Mtb) is the causative agent of tuberculosis and one of the top infectious killers in the world, with around 1.3 million deaths reported annually. The genetic variability of this pathogen can shape its interaction with the host and modulate disease outcomes. We previously found that Mtb clinical isolates from patients with severe forms of tuberculosis evade cytosolic surveillance systems in macrophages. Here, we explored whether this evasion tactic was linked to metabolic alterations in the infected macrophages. We found that different Mtb isolates induced similar metabolic changes in infected macrophages. Additionally, we demonstrate that both host glycolysis and pathogen’s metabolism were pivotal for maximum IL-1β production. These findings highlight the complexity of macrophage-pathogen interactions and emphasize that bacterial metabolism should be considered in metabolic studies and may be amenable to therapeutic intervention against tuberculosis.