SUMMARY Induction of trained immunity (innate immune memory) is mediated by activation of immune and metabolic pathways that result in epigenetic rewiring of cellular functional programs. Through network-level integration of transcriptomics and metabolomics data, we identify glycolysis, glutaminolysis, and the cholesterol synthesis pathway as indispensable for the induction of trained immunity by β-glucan in monocytes. Accumulation of fumarate, due to glutamine replenishment of the TCA cycle, integrates immune and metabolic circuits to induce monocyte epigenetic reprogramming by inhibiting KDM5 histone demethylases. Furthermore, fumarate itself induced an epigenetic program similar to β-glucan-induced trained immunity. In line with this, inhibition of glutaminolysis and cholesterol synthesis in mice reduced the induction of trained immunity by β-glucan. Identification of the metabolic pathways leading to induction of trained immunity contributes to our understanding of innate immune memory and opens new therapeutic avenues.

In response to infection, macrophages adapt their metabolism rapidly to enhance glycolysis and fuel specialized antimicrobial effector functions. Here we show that fungal melanin is an essential molecule required for the metabolic rewiring of macrophages during infection with the fungal pathogen Aspergillus fumigatus. Using pharmacological and genetic tools, we reveal a molecular link between calcium sequestration by melanin inside the phagosome and induction of glycolysis required for efficient innate immune responses. By remodeling the intracellular calcium machinery and impairing signaling via calmodulin, melanin drives an immunometabolic signaling axis towards glycolysis with activation of hypoxia-inducible factor 1 subunit alpha (HIF-1α) and phagosomal recruitment of mammalian target of rapamycin (mTOR). These data demonstrate a pivotal mechanism in the immunometabolic regulation of macrophages during fungal infection and highlight the metabolic repurposing of immune cells as a potential therapeutic strategy.

Highlights d HIF-1a is a protective factor against Leishmania donovani infection d In absence of HIF-1a, lipogenesis is induced via BNIP3/ mTOR/SREBP-1c modulation d Blockage of lipogenesis reverts HIF-1a-associated Leishmania susceptibility d HIF1A polymorphism correlates with susceptibility to infection

Nicotinamide adenine dinucleotide (NAD ?) is a vital molecule found in all living cells. NAD ? intracellular levels are dictated by its synthesis, using the de novo and/or salvage pathway, and through its catabolic use as co-enzyme or co-substrate. The regulation of NAD ? metabolism has proven to be an adequate drug target for several diseases, including cancer, neurodegenerative or inflammatory diseases. Increasing interest has been given to NAD ? metabolism during innate and adaptive immune responses suggesting that its modulation could also be relevant during host-pathogen interactions. While the maintenance of NAD ? homeostatic levels assures an adequate environment for host cell survival and proliferation, fluctuations in NAD ? or biosynthetic precursors bioavailability have been described during host-pathogen interactions, which will interfere with pathogen persistence or clearance. Here, we review the double-edged sword of NAD ? metabolism during host-pathogen interactions emphasizing its potential for treatment of infectious diseases. Keywords Nicotinamide adenine dinucleotide (NAD ?) Á Host-pathogen interaction Á NAD ? /NADH ratio Á NADPH Á Sirtuins Á L-tryptophan Nicotinamide adenine dinucleotide (NAD ?) was initially discovered by Sir Arthur Harden as a 'cozymase' for yeast fermentation over 100 years ago. The succeeding work contributed to the identification of NAD ? as a player in hundreds of biochemical reactions through its role in redox reactions. NAD ? is either consumed as a co-substrate by NAD ?-consuming enzymes or used as an electron carrier in redox reactions. Yet, the intracellular NAD ? /NADH ratio is key to the maintenance of an adequate metabolic status and cell survival. Growing evidences indicate that NAD ? biosynthetic pathways and metabolism are playing a major role in hostpathogen interactions. In this review, we overview these mechanisms highlighting the role of NAD ? metabolism as an attractive therapeutic target for microbe infections. NAD 1 biosynthesis: where the tale begins NAD 1 biosynthesis in mammalian cells The biosynthesis of NAD ? in mammals occurs through two different pathways: the de novo and the salvage pathways (Fig. 1). The de novo pathway begins with the uptake and conversion of dietary L-tryptophan in N-formylkynurenine, which is mediated by the rate-limiting indoleamine 2,3-dioxygenase (IDO) or tryptophan 2,3

Similar efficacy with omalizumab in chronic idiopathic/spontaneous urticaria despite different background therapy.