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.

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

It is well established that CD8+ T cells play an important role in protective immunity against protozoan infections. However, their role in the course of Neospora caninum infection has not been fully elucidated. Here we report that CD8-deficient mice infected with N. caninum presented higher parasitic loads in the brain and lungs and lower spleen and brain immunity-related GTPases than their wild-type counterparts. Moreover, adoptive transfer of splenic CD8+ T cells sorted from N. caninum-primed immunosufficient C57BL/10 ScSn mice prolonged the survival of infected IL-12-unresponsive C57BL/10 ScCr recipients. In both C57BL/6 and C57BL/10 ScSn mice CD8+ T cells are activated and produce interferon-γ (IFN-γ) upon challenged with N. caninum. The host protective role of IFN-γ produced by CD8+ T cells was confirmed in N. caninum-infected RAG2-deficient mice reconstituted with CD8+ T cells obtained from either IFN-γ-deficient or wild-type donors. Mice receiving IFN-γ-expressing CD8+ T cells presented lower parasitic burdens than counterparts having IFN-γ-deficient CD8+ T cells. Moreover, we observed that N. caninum-infected perforin-deficient mice presented parasitic burdens similar to those of infected wild-type controls. Altogether these results demonstrate that production of IFN-γ is a predominant protective mechanism conferred by CD8+ T cells in the course of neosporosis.