Immunometabolic Pathways in BCG-Induced Trained Immunity

Abstract

SummaryThe protective effects of the tuberculosis vaccine Bacillus Calmette-Guerin (BCG) on unrelated infections are thought to be mediated by long-term metabolic changes and chromatin remodeling through histone modifications in innate immune cells such as monocytes, a process termed trained immunity. Here, we show that BCG 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. Pharmacological and genetic modulation of rate-limiting glycolysis enzymes inhibits trained immunity, changes that are reflected by the effects on the histone marks (H3K4me3 and H3K9me3) underlying BCG-induced trained immunity. These data demonstrate that a shift of the glucose metabolism toward glycolysis is crucial for the induction of the histone modifications and functional changes underlying BCG-induced trained immunity. The identification of these pathways may be a first step toward vaccines that combine immunological and metabolic stimulation.

Defining a Research Agenda to Address the Converging Epidemics of Tuberculosis and Diabetes

“…Another study showed how responses to BCG depend on changes in cellular metabolism and epigenetics. 36 These findings reveal a novel regulatory layer of host responses to M. tuberculosis that could be exploited for host-directed therapy. Indeed, the antidiabetic drug metformin, which inhibits mTOR through induction of AMPK (adenosine monophosphate-activated protein kinase), was shown to increase mitochondrial reactive oxygen species, facilitate phagosomelysosome fusion and reduce growth of M. tuberculosis in macrophages.…”

Immunity against fungi

“…During repetitive challenges with β-glucans, murine Ly6C hi monocytes and human CD14 + monocytes exhibit attributes reminiscent of immunologic memory, including enhanced responsiveness, based on cytokine responses (102). β-Glucan priming induces epigenetic and metabolic changes in monocytes, the latter of which associates with a shift from oxidative phosphorylation to glycolysis via a dectin-1/AKT/mTOR/HIF-1α signaling pathway (103) and increased glutaminolysis (104). In macrophages, β-glucan priming partially reverses LPS exposure-associated chromatin modifications, specifically the silencing of proinflammatory genes (105).…”

MTBVAC from discovery to clinical trials in tuberculosis-endemic countries

“…And most recently, Arts et al [31], showed essential roles for metabolic pathways in BCG induced trained immunity in human monocytes. Moreover, induction of these pathways is regulated by epigenetic mechanisms at the level of chromatin organization, calling for future studies on the potential therapeutic role that the modulation of these pathways may have during vaccination [31]. Finally, most European countries where incidence of TB is now low, have relinquished BCG from their vaccination schedule or restricted it to highrisk groups; however, subsequent studies suggest that this policy may have increased the incidence of a wide variety of conditions, including atopic dermatitis [12].…”

“…Moreover, these effects are shown to be mediated by the functional and epigenetic reprogramming of innate immune cells such as monocytes, macrophages, and NK (natural killer) cells, a process termed 'trained immunity' [29,30]. And most recently, Arts et al [31], showed essential roles for metabolic pathways in BCG induced trained immunity in human monocytes. Moreover, induction of these pathways is regulated by epigenetic mechanisms at the level of chromatin organization, calling for future studies on the potential therapeutic role that the modulation of these pathways may have during vaccination [31].…”