Evolutionary Views of Tuberculosis: Indoleamine 2,3‐Dioxygenase Catalyzed Nicotinamide Synthesis Reflects Shifts in Macrophage Metabolism

Abstract

Indoleamine 2,3-dioxygenase (IDO) is the rate-limiting enzyme in conversion of tryptophan to kynurenines, feeding de novo nicotinamide synthesis. IDO orchestrates materno-foetal tolerance, increasing human reproductive fitness. IDO mediates immune suppression through depletion of tryptophan required by T lymphocytes and other mechanisms. IDO is expressed by alternatively activated macrophages, suspected to play a key role in tuberculosis (TB) pathogenesis. Unlike its human host, Mycobacterium tuberculosis can synthesize tryptophan, suggesting possible benefit to the host from infection with the microbe. Intriguingly, nicotinamide analogues are used to treat TB. In reviewing this field, it is postulated that flux through the nicotinamide synthesis pathway reflects switching between aerobic glycolysis and oxidative phosphorylation in M. tuberculosis-infected macrophages. The evolutionary cause of such shifts may be ancient mitochondrial behavior related to reproductive fitness. Evolutionary perspectives on the IDO pathway may elucidate why, after centuries of co-existence with the Tubercle bacillus, humans still remain susceptible to TB disease.

The Kynurenine Pathway—New Linkage between Innate and Adaptive Immunity in Autoimmune Endocrinopathies

“…It has been reported that AhR-deficient macrophages showed a higher level of proinflammatory cytokines upon LPS stimulation and that AhR-deficient mice were more susceptible to LPS-induced lethal shock than wild-type mice [96]. Recently, Suchard et coworkers [97] summarized existing literature and showed that elevated IDO1 activity is regarded as a feature of M2 macrophage activation.…”

Nicotinamide pathways as the root cause of sepsis – an evolutionary perspective on macrophage energetic shifts

“…As prokaryotes, bacteria have their own unique pathways of NAD synthesis. Commensal and pathogenic flora form a complex cycle of NAD synthesis and consumption, which may regulate the pathogen-host balance [63] [19]. As an example, tuberculosis necrotizing toxin, secreted by Mycobacterium tuberculosis, with homologues in many bacterial and fungal pathogens, hydrolyses NAD + and results in cellular death by necroptosis [64].…”

“…As an example, tuberculosis necrotizing toxin, secreted by Mycobacterium tuberculosis, with homologues in many bacterial and fungal pathogens, hydrolyses NAD + and results in cellular death by necroptosis [64]. Mycobacterium tuberculosis can also synthesize niacin [65], leading to postulates that latent Mycobacterium tuberculosis has beneficial effects for the human host by increasing nicotinamide availability [66] [63].…”

“…Indeed, pyrazinamide – another antituberculosis agent – has downstream metabolites, which convert nicotinamide to NAD + [10]. Thus, at least some of the efficacy of isoniazid and pyrazinamide for treatment of sepsis caused by tuberculosis may be due to interactions of the drugs with NAD synthesis and salvage [63].…”

The Kynurenine/Tryptophan Ratio Is a Sensitive Biomarker for the Diagnosis of Pediatric Tuberculosis Among Indian Children

“…The resulting ratio of kynurenine to tryptophan (K/T) has therefore been proposed as a potential biomarker for the diagnosis of TB that was also associated with treatment outcomes. The decline in tryptophan is associated with the induction of immunoregulatory enzyme indoleamine 2,3-dioxygenase (IDO-1), which breaks down tryptophan to kynurenine metabolites and suppresses the immune response, particularly through shifts in macrophage metabolism and induction of T-cell anergy and apoptosis ( 8 , 9 ). Metabolic changes in this pathway have also been identified among those with latent TB infection, as well as in multidrug-resistant TB, cavitary disease, and extrapulmonary TB, with low tryptophan in the cerebrospinal fluid of people with tuberculous meningitis ( 7 , 10 ).…”