Opposing Biological Functions of Tryptophan Catabolizing Enzymes During Intracellular Infection

Divanovic, Senad; Sawtell, Nancy; Trompette, Aurélien; Warning, Jamie I.; Dias, Armando Cavalcante Franco; Cooper, Andrea M.; Yap, George; Arditi, Moshe; Shimada, Kenichi; DuHadaway, James B.; Prendergast, George C.; Basaraba, Randall J.; Mellor, Andrew L.; Munn, David H.; Aliberti, Júlio; Karp, Christopher L.

doi:10.1093/infdis/jir621

Cited by 104 publications

(107 citation statements)

References 52 publications

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“…In vivo blocking of IDO increases the burden of parasites such as T. gondii (18) and Trypanosoma cruzi (41) and of fungi (Candida albicans (42)) in mice, which seems consistent with its antimicrobial role in vitro. In contrast, inhibition or deficiency of enzyme during other parasitic (Leishmania donovani (18) and Trichuris muris (43)) and bacterial (Citrobacter rodentium (44)) infections reduced the pathogen burden in animals.…”

Section: Discussionmentioning

confidence: 52%

“…In contrast, inhibition or deficiency of enzyme during other parasitic (Leishmania donovani (18) and Trichuris muris (43)) and bacterial (Citrobacter rodentium (44)) infections reduced the pathogen burden in animals. Moreover, 1-MT, a competitive inhibitor of IDO, had none (herpes simplex virus 1) to a negative (BM5) influence on the virus replication in mice (18,45), which occasionally differs with in vitro findings (46). Likewise, IDO1 as a positive determinant of Eimeria growth does not reconcile with canonical antimicrobial function, notwithstanding a potential depletion of tryptophan in the infected host cell.…”

Section: Discussionmentioning

confidence: 99%

“…The immunosuppressive role of IDO1 is thought to be mediated by inhibition of the T-cell proliferation as a consequence of tryptophan starvation (5,6,14) and/or due to an elevated apoptosis inflicted by kynurenine metabolites (15)(16)(17). Besides, blocking of IDO exerted no apparent effect on the mouse immune response in a toxoplasmosis model, whereas an increase in IFN␥ and a decrease in IL-10 level were observed in Leishmania-infected animals (18). It is thus debatable whether an induced expression of IDO is required for the host resistance against the pathogens and/or for antiproliferative effects to counteract an escalated immune response.…”

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confidence: 99%

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Apicomplexan Parasite, Eimeria falciformis, Co-opts Host Tryptophan Catabolism for Life Cycle Progression in Mouse

Schmid

Lehmann

Lucius

et al. 2012

Journal of Biological Chemistry

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Background:The kynurenine pathway catalyzes tryptophan catabolism in mammals. Results: The rate-limiting indoleamine 2,3-dioxygenase and two other enzymes of the host kynurenine pathway are required for an efficient development of the apicomplexan parasite E. falciformis in mouse. Conclusion: A previously unanticipated pro-parasite function of host tryptophan catabolism is revealed. Significance: An intracellular pathogen subverts the host defense (IFN␥, IDO1) for progression of natural life cycle.

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Section: Discussionmentioning

confidence: 52%

Section: Discussionmentioning

confidence: 99%

mentioning

confidence: 99%

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Apicomplexan Parasite, Eimeria falciformis, Co-opts Host Tryptophan Catabolism for Life Cycle Progression in Mouse

Schmid

Lehmann

Lucius

et al. 2012

Journal of Biological Chemistry

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“…In particular, IDOtryptophan-directed immunosuppression is thought to play a role in infections by Leishmania major (90), human immunodeficiency virus (reviewed in reference 91), hepatitis C virus (92,93), human papillomavirus (94), Listeria monocytogenes (95), Mycobacterium tuberculosis (96), Candida albicans (97), and Aspergillus fumigatus (98). Importantly, a recent study investigating the role IDO plays in infections by two protozoal species, T. gondii and L. major, found that IDO facilitates T. gondii clearance and suppresses L. major clearance, highlighting the opposing and pathogen-specific roles that IDO can have in infectious disease (90).…”

Section: Pathogen Defence Via Ido (Indoleamine 23-dioxygenase)-mediamentioning

confidence: 99%

Evolution to a Chronic Disease Niche Correlates with Increased Sensitivity to Tryptophan Availability for the Obligate Intracellular Bacterium Chlamydia pneumoniae

Huston

Barker

Chacko

2014

Journal of Bacteriology

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bThe chlamydiae are obligate intracellular parasites that have evolved specific interactions with their various hosts and host cell types to ensure their successful survival and consequential pathogenesis. The species Chlamydia pneumoniae is ubiquitous, with serological studies showing that most humans are infected at some stage in their lifetime. While most human infections are asymptomatic, C. pneumoniae can cause more-severe respiratory disease and pneumonia and has been linked to chronic diseases such as asthma, atherosclerosis, and even Alzheimer's disease. The widely dispersed animal-adapted C. pneumoniae strains cause an equally wide range of diseases in their hosts. It is emerging that the ability of C. pneumoniae to survive inside its target cells, including evasion of the host's immune attack mechanisms, is linked to the acquisition of key metabolites. Tryptophan and arginine are key checkpoint compounds in this host-parasite battle. Interestingly, the animal strains of C. pneumoniae have a slightly larger genome, enabling them to cope better with metabolite restrictions. It therefore appears that as the evolutionarily more ancient animal strains have evolved to infect humans, they have selectively become more "susceptible" to the levels of key metabolites, such as tryptophan. While this might initially appear to be a weakness, it allows these human C. pneumoniae strains to exquisitely sense host immune attack and respond by rapidly reverting to a persistent phase. During persistence, they reduce their metabolic levels, halting progression of their developmental cycle, waiting until the hostile external conditions have passed before they reemerge.

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“…When the therapeutic inhibition of IDO-1 is considered, it is important to mention that IDO-1 can have contradictory functions: it can exert immunoregulatory (Leishmania major) and antimicrobial (Toxoplasma gondii, Trypanosoma cruzi) effects, which are specific for the individual pathogen (31), with the molecular mechanisms being largely unknown. The most frequently used IDO inhibitor is 1-methyl-D-tryptophan (1-MDT), which has reached phase 1 clinical trials as an adjunct to conventional chemotherapy of cancer, since many tumors express IDO for immune suppression (15).…”

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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Opposing Biological Functions of Tryptophan Catabolizing Enzymes During Intracellular Infection

Cited by 104 publications

References 52 publications

Apicomplexan Parasite, Eimeria falciformis, Co-opts Host Tryptophan Catabolism for Life Cycle Progression in Mouse

Apicomplexan Parasite, Eimeria falciformis, Co-opts Host Tryptophan Catabolism for Life Cycle Progression in Mouse

Evolution to a Chronic Disease Niche Correlates with Increased Sensitivity to Tryptophan Availability for the Obligate Intracellular Bacterium Chlamydia pneumoniae

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

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