IRG1 controls host responses to restrict Mycobacterium tuberculosis infection

Abstract

Mycobacterium tuberculosis (Mtb), the pathogen causing human tuberculosis, has evolved multiple strategies to successfully prevent clearance by immune cells and to establish dissemination and long-term survival in the host. The modulation of host immunity to maximize pathogen elimination while minimizing inflammation-mediated tissue damage may provide another tool to fight drug-resistant Mtb strains.Metabolic reprogramming of immune cell populations can dramatically influence the outcome of immune responses and modulate antimicrobial properties of infected host cells, nicely demonstrating that metabolites are tightly linked to immune cell effector functions. One important endogenous metabolite of the Krebs cycle is itaconate, which has potent bactericidal activity by inhibiting isocitrate lyase and the glyoxylate shunt within prokaryotes including mycobacteria. Recent findings show that itaconate and the catalytic enzyme responsible for its generation in mammalian cells, i.e. IRG1 (immune-responsive gene 1), also modify inflammatory signaling of infected cells enhancing host defense pathways.Here, we demonstrate that IRG1 is recruited to Mtb-containing phagosomes and that it influences the host response controlling Mtb infection. While IRG1 deficiency does not affect uptake of Mtb by macrophages and dendritic cells (DCs) in vitro, it increases the intracellular replication of Mtb. Concomitantly, in comparison to wild type cells, IRG1-deficient macrophages and DCs have increased levels of lipid droplets, a correlate of inflammation. These intracellular organelles store triacylglycerol and phospholipids that are hijacked by Mtb as reservoir of host nutrients. Exposure of IRG1-deficient mice to M. bovis BCG via the intranasal route induced neither lethality nor severe lung immunopathology, while IRG1-deficient mice were highly susceptible to Mtb infection resulting in animal death three weeks post-infection linked to exacerbated inflammation and high mycobacterial burden. The lungs of infected IRG1-deficient mice displayed large areas of necrotizing granulomatous inflammation and neutrophil infiltration, accompanied by reduced levels of B and T lymphocytes and increased levels of alveolar and interstitial macrophage populations, compared to their wild type counterparts. Therefore, our findings demonstrate that IRG1 is a major player in controlling the acute phase of Mtb infection with a specific effect on pathogenic mycobacteria.

Not too fat to fight: The emerging role of macrophage fatty acid metabolism in immunity to Mycobacterium tuberculosis

“…18 In macrophages, infection with Mtb downregulated IDH production while increasing expression and activity of IRG1, thus promoting the production of itaconate. 19 Yet, itaconate has antiinflammatory effects in activated macrophages, through inhibition of the production of inflammatory cytokines and reactive oxygen species (ROS). 20,21 In addition, itaconate was shown to be a potent inhibitor of isocitrate lyases Icl1/2 in Mtb.…”

“…TLR4 activation also induces a break point in the TCA cycle at isocitrate dehydrogenase (IDH), diverting the cis‐aconitate substrate of IDH toward production of itaconate by aconitate decarboxylase, also known as immune‐responsive‐gene 1 (IRG1) 18 . In macrophages, infection with Mtb downregulated IDH production while increasing expression and activity of IRG1, thus promoting the production of itaconate 19 . Yet, itaconate has anti‐inflammatory effects in activated macrophages, through inhibition of the production of inflammatory cytokines and reactive oxygen species (ROS) 20,21 .…”

“…Products of the glyoxylate shunt fuel gluconeogenesis in Mtb when FAs are the only available carbon sources, and this metabolic pathway was found critical for bacterial growth in vivo 23 . Notably, IRG1‐deficient macrophages were defective in their ability to control intracellular Mtb growth 19 and IRG1 expression prevented immunopathology in a mouse model of Mtb infection, 24 demonstrating the importance of this pathway in host defense against Mtb. Reprogramming of aerobic glycolysis and TCA cycle is associated with increased levels of NADPH oxidase and inducible nitric oxide synthase (iNOS), promoting the production of ROS including nitric oxide (NO) with antimycobacterial activity 25,26 .…”

Reversing Post-Infectious Epigenetic-Mediated Immune Suppression

“…that converts citrate to itaconate) have increased proinflammatory cytokine production (IL1b, IL-6, IFN-y, IL12) and fatal exuberant pulmonary infiltration of innate immune cells (94,95).…”

“…Upon immune activation via mTOR and NFAT signaling, shifts in cellular metabolism increase glycolysis, the tricarboxylic acid cycle (TCA, also known as the Krebs cycle) and electron transport chain (ETC), not only to meet high energy demands for proliferation and effector function, but also to produce the intermediate metabolites that fuel the biosynthesis of effector protein functions ( 10 , 89 – 91 ). While initially beneficial, in severe or chronic infection, these metabolic shifts contribute to epigenetic changes that induce immune suppression ( 35 , 89 , 90 , 92 – 95 ). In both lymphoid and myeloid cells, these metabolic shifts are mediated by the PI3K-Akt-mTOR pathway ( 96 ) and if the infection persists, the associated signaling cascades are downregulated and epigenetic mechanisms suppress host immunity, with loss of accessible chromatin that allows for expression of cytokines such as Tnf and Ifng and gain of chromatin accessible regions in inhibitory loci such as Pdcd1 ( 97 , 98 ), thereby placing cells into an immune suppressed state ( 97 ).…”