M. tuberculosis Induces Potent Activation of IDO-1, but This Is Not Essential for the Immunological Control of Infection

Blumenthal, Antje; Nagalingam, Gayathri; Huch, Jennifer H.; Walker, Lara; Guillemin, Gilles J.; Smythe, George A.; Ehrt, Sabine; Britton, Warwick J.; Saunders, Bernadette M.

doi:10.1371/journal.pone.0037314

Cited by 80 publications

(90 citation statements)

References 52 publications

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“…Despite the elevated expression of IDO1 within lung airway epithelial cells, vascular endothelial cells, macrophages and DCs of M. tuberculosis-infected mice [464,465], wild-type and IDO1 −/− mice have similar bacterial burdens, inflammatory responses and levels of T-cell activation, with no difference in survival between the two strains [464]. A recent important study [466] provides an explanation for why IDO1 −/− mice and wild-type mice have similar bacterial burdens [464]. Zhang et al [466] established that an important determinant underlying the ability of M. tuberculosis to withstand host immunity is the bacterium's capacity to synthesise L-Trp, thereby making the microbe refractory to IDO1-catalysed L-Trp starvation [466].…”

Section: Micro-organism Induction Of Ido1 In Vivomentioning

confidence: 93%

“…However, certain T-cell subsets such as inflammatory Th17 cells appear more sensitive to Kyn metabolites than M. tuberculosis, suggesting that IDO1 may exhibit a more prominent immunosuppressive effect in favour of the mycobacterium. Despite the elevated expression of IDO1 within lung airway epithelial cells, vascular endothelial cells, macrophages and DCs of M. tuberculosis-infected mice [464,465], wild-type and IDO1 −/− mice have similar bacterial burdens, inflammatory responses and levels of T-cell activation, with no difference in survival between the two strains [464]. A recent important study [466] provides an explanation for why IDO1 −/− mice and wild-type mice have similar bacterial burdens [464].…”

Section: Micro-organism Induction Of Ido1 In Vivomentioning

confidence: 99%

“…In vitro studies have shown that the growth of M. tuberculosis is suppressed by particular Kyn pathway metabolites (e.g. 100 μM picolinic acid at a pH of 5.5 to mimic the conditions in an acidified phagosome) [464]. However, certain T-cell subsets such as inflammatory Th17 cells appear more sensitive to Kyn metabolites than M. tuberculosis, suggesting that IDO1 may exhibit a more prominent immunosuppressive effect in favour of the mycobacterium.…”

Section: Micro-organism Induction Of Ido1 In Vivomentioning

confidence: 99%

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Role of indoleamine 2,3-dioxygenase in health and disease

et al. 2015

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IDO1 (indoleamine 2,3-dioxygenase 1) is a member of a unique class of mammalian haem dioxygenases that catalyse the oxidative catabolism of the least-abundant essential amino acid, L-Trp (L-tryptophan), along the kynurenine pathway. Significant increases in knowledge have been recently gained with respect to understanding the fundamental biochemistry of IDO1 including its catalytic reaction mechanism, the scope of enzyme reactions it catalyses, the biochemical mechanisms controlling IDO1 expression and enzyme activity, and the discovery of enzyme inhibitors. Major advances in understanding the roles of IDO1 in physiology and disease have also been realised. IDO1 is recognised as a prominent immune regulatory enzyme capable of modulating immune cell activation status and phenotype via several molecular mechanisms including enzyme-dependent deprivation of L-Trp and its conversion into the aryl hydrocarbon receptor ligand kynurenine and other bioactive kynurenine pathway metabolites, or non-enzymatic cell signalling actions involving tyrosine phosphorylation of IDO1. Through these different modes of biochemical signalling, IDO1 regulates certain physiological functions (e.g. pregnancy) and modulates the pathogenesis and severity of diverse conditions including chronic inflammation, infectious disease, allergic and autoimmune disorders, transplantation, neuropathology and cancer. In the present review, we detail the current understanding of IDO1's catalytic actions and the biochemical mechanisms regulating IDO1 expression and activity. We also discuss the biological functions of IDO1 with a focus on the enzyme's immune-modulatory function, its medical implications in diverse pathological settings and its utility as a therapeutic target.

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Section: Micro-organism Induction Of Ido1 In Vivomentioning

confidence: 93%

Section: Micro-organism Induction Of Ido1 In Vivomentioning

confidence: 99%

Section: Micro-organism Induction Of Ido1 In Vivomentioning

confidence: 99%

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Role of indoleamine 2,3-dioxygenase in health and disease

et al. 2015

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“…Possibly IDO-induced tryptophan depletion inhibits Mtb replication in RPE, but this would require further study. 26 In contrast, excessive IFNa/b signaling has been linked to high Mtb disease activity in patients with clinical disease. 18,19 Suppression of cytokines crucial for host defense against Mtb, including IL-1a, IL-1b, IL-12, and TNFa, and also repression of innate cell responsiveness to IFNc, have been proposed as important mechanisms of IFNa/b-mediated immunosuppression during Mtb infection.…”

Section: Discussionmentioning

confidence: 99%

Retinal Pigment Epithelial Cells Control Early Mycobacterium tuberculosis Infection via Interferon Signaling

Nora

Walburg

Hagen

et al. 2018

Invest. Ophthalmol. Vis. Sci.

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METHODS. To address a potential role for Mtb-infected RPE cells in the development of uveitis, we delineated the response to Mtb infection in human RPE cells and primary human macrophages, the main target cell of Mtb. Primary human RPE cells, the human RPE cell line ARPE-19, and monocyte-derived proinflammatory M1 and anti-inflammatory M2 macrophages were infected with DsRed-expressing Mtb strain H37Rv. Infection rates and clearance were addressed along with RNA sequencing analysis, a confirmation analysis by dual-color reverse-transcriptase multiplex ligation-dependent probe amplification (dcRT-MLPA) and cytokine secretion.RESULTS. RPE cells robustly controlled intracellular outgrowth of Mtb early after infection. The response in RPE cells to control Mtb survival was dominated by interferon (IFN) signaling and further characterized by prominent regulation of cell death/survival-associated genes and low-level production of Th1-associated cytokines. In contrast, macrophages engaged a plethora of responses including IFN signaling and communication between innate and adaptive immune cells to induce granuloma formation. CONCLUSIONS.Together, our data demonstrate that RPE cells display a strong response to Mtb infection that appears, however, incomplete in comparison to the macrophage response to Mtb. The RPE response might reflect a balance between mechanisms aimed at Mtb eradication and mechanisms that limit retinal inflammation.

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“…IDO-1 expression and activity are increased in the brains of mice during CM (25,27), and IFN-␥, an important regulator of IDO-1, is a central element in the pathogenesis of CM (25,29), although mice genetically deficient in IDO-1 do not seem to be protected against CM (9). Similarly, Mycobacterium tuberculosis infection induces IDO-1 expression and, thus, tryptophan metabolism, but a lack of IDO-1 activity did not affect survival after M. tuberculosis infection (30). Although its expression is not elevated during CM (13), IDO-2 might be able to compensate for a lack of IDO-1 activity.…”

mentioning

confidence: 99%

Benzo[ b ]quinolizinium Derivatives Have a Strong Antimalarial Activity and Inhibit Indoleamine Dioxygenase

Jortzik

Zocher

Isernhagen

et al. 2016

Antimicrob Agents Chemother

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eThe heme-containing enzymes indoleamine 2,3-dioxygenase-1 (IDO-1) and IDO-2 catalyze the conversion of the essential amino acid tryptophan into kynurenine. Metabolites of the kynurenine pathway and IDO itself are involved in immunity and the pathology of several diseases, having either immunoregulatory or antimicrobial effects. IDO-1 plays a central role in the pathogenesis of cerebral malaria, which is the most severe and often fatal neurological complication of infection with Plasmodium falciparum. Mouse models are usually used to study the underlying pathophysiology. In this study, we screened a natural compound library against mouse IDO-1 and identified 8-aminobenzo[b]quinolizinium (compound 2c) to be an inhibitor of IDO-1 with potency at nanomolar concentrations (50% inhibitory concentration, 164 nM). Twenty-one structurally modified derivatives of compound 2c were synthesized for structure-activity relationship analyses. The compounds were found to be selective for IDO-1 over IDO-2. We therefore compared the roles of prominent amino acids in the catalytic mechanisms of the two isoenzymes via homology modeling, site-directed mutagenesis, and kinetic analyses. Notably, methionine 385 of IDO-2 was identified to interfere with the entrance of L-tryptophan to the active site of the enzyme, which explains the selectivity of the inhibitors. Most interestingly, several benzo[b]quinolizinium derivatives (6 compounds with 50% effective concentration values between 2.1 and 6.7 nM) were found to be highly effective against P. falciparum 3D7 blood stages in cell culture with a mechanism independent of IDO-1 inhibition. We believe that the class of compounds presented here has unique characteristics; it combines the inhibition of mammalian IDO-1 with strong antiparasitic activity, two features that offer potential for drug development.T ryptophan metabolism along the kynurenine (Kyn) pathway is a central component in neurodegenerative disorders and neuronal damage. The main metabolites of the kynurenine pathway include kynurenic acid, an antagonist of glutamate and nicotinic receptors; quinolinic acid, an agonist of N-methyl-D-aspartate receptors; and picolinic acid. Due to its potential role in diseases such as cancer (1), Alzheimer's disease (2), depression (3), stroke (4), and HIV infections (5), the kynurenine pathway is intensely studied with regard to chemotherapeutic applications in humans. Moreover, the pathway has been implicated in parasitic infections, such as trypanosomiasis (6), toxoplasmosis (7,8), and cerebral malaria (CM), as shown in mouse model systems (9, 10). CM is a potentially fatal consequence of infection with Plasmodium falciparum and can lead, in case of survival, to neurological or cognitive deficits (10). Severe malaria remains a global health problem. Although the mortality rate decreased by about 25% between 2000 and 2010, malaria caused 627,000 deaths in 2012. Currently, no specific treatment for CM is available, but a couple of immunomodulatory therapies are under investigation (11).As a...

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M. tuberculosis Induces Potent Activation of IDO-1, but This Is Not Essential for the Immunological Control of Infection

Cited by 80 publications

References 52 publications

Role of indoleamine 2,3-dioxygenase in health and disease

Role of indoleamine 2,3-dioxygenase in health and disease

Retinal Pigment Epithelial Cells Control Early Mycobacterium tuberculosis Infection via Interferon Signaling

Benzo[ b ]quinolizinium Derivatives Have a Strong Antimalarial Activity and Inhibit Indoleamine Dioxygenase

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