Immunometabolic Pathways in BCG-Induced Trained Immunity

We show that Bacillus Calmette-Guerin induction of trained immunity in monocytes is accompanied by a strong increase in glycolysis and, to a lesser extent, glutamine metabolism, both in an in-vitro model and after vaccination of mice and humans

Rob J.W. Arts; Agostinho Carvalho; Claudia La Rocca; Carla Palma; Fernando Rodrigues; Ricardo Silvestre; Johanneke Kleinnijenhuis; Ekta Lachmandas; Luís G. Gonçalves; Ana Belinha; Cristina Cunha; Marije Oosting; Leo A.B. Joosten; Giuseppe Matarese; Reinout van Crevel; Mihai G. Netea

2016

Scholarcy highlights

  • The live attenuated Bacillus Calmette-Guerin vaccine confers protection against severe forms of Mycobacterium tuberculosis infection while having a limited effect against pulmonary tuberculosis
  • We have recently demonstrated that induction of trained immunity by fungal components such as b-glucan leads to a shift of cellular metabolism from oxidative phosphorylation toward glucose fermentation
  • Metabolic Changes and Trained Immunity Are Dependent on Activation of the Akt-mTOR Pathway We previously showed that the shift toward a higher glycolytic rate in b-glucan-induced trained monocytes is dependent on the Akt/mTOR pathway
  • The inhibition of the electron transport chain by the complex V inhibitor oligomycin did Epigenetic Regulation of Metabolism To further assess how glucose and glutamine metabolism are regulated in BCGtrained monocytes and macrophages, mRNA expression of mTOR and four essential enzymes in glycolysis and glutamine metabolism were determined at day 6 after BCG training. mTOR and all four enzymes were upregulated in trained monocytes prior to restimulation
  • Genetic Validation for a Role of Glycolysis Pathway in Trained Immunity As a final step, we examined whether genetic variation in metabolic pathways affected in vitro training of monocytes by BCG: if glycolysis and glutaminolysis are important for the induction of trained immunity, genetic variation of rate-limiting enzymes in these pathways should modulate trained immunity
  • We show that the change in inflammatory profile and the underlying epigenetic changes are dependent on changes in cellular metabolism, with an increase in glycolysis as central hallmark, and with the upregulation of glutamine metabolism and oxidative phosphorylation
  • The identification of these pathways may be a first step toward vaccines that combine immunological and metabolic stimulation

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