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

Schmid, Manuela; Lehmann, Maik J.; Lucius, Richard; Gupta, Nishith

doi:10.1074/jbc.m112.351999

Cited by 25 publications

(34 citation statements)

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“…falciformis BayerHaberkorn1970 (Haberkorn, 1970) Between the two E. falciformis isolates BayerHaberkorn1970 and Brandenburg88 we observed only slight differences in the length of the pre-patent period (time until oocyst shedding, starting at 6 vs. 7 dpi). These results are in agreement with previous reports from the same host (NMRI mice) and the BayerHaberkorn1970 isolate (Stange et al, 2012;Schmid et al, 2012Schmid et al, , 2014Ehret et al, 2017). The pre-patent period for the wild derived E. falciformis isolate (7 dpi) corresponds to that reported for the parasite isolate E. falciformis var praghensis (Mesfin et al, 1978;Kasai et al, 1991), but Mahrt and Shi (1988) and Schito et al (1996) demonstrated slightly longer pre-patent periods (7 or 8 dpi) also in other E. falciformis infections.…”

Section: Discussionsupporting

confidence: 94%

“…The isolate E. falciformis BayerHaberkorn1970 has been isolated in 1960 (Haberkorn 1970) and since has been propagated in laboratories (first at Bayer animal health, Monheim, Germany; then at the institute for molecular parasitology of the Humboldt University, Berlin, Germany). In nearly 60 years since its isolation E. falciformis BayerHaberkorn1970 has likely become the most commonly used laboratory isolate of rodent Eimeria (Mahrt and Shi 1988;Schito et al, 1996;Steinfelder et al, 2005;Pogonka et al, 2010;Stange et al, 2012;Schmid et al, 2014Schmid et al, , 2012Ehret et al, 2017).…”

Section: Introductionmentioning

confidence: 99%

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Eimeria falciformisBayerHaberkorn1970 and novel wild derived isolates from house mice: differences in parasite lifecycle, pathogenicity and host immune reactions

Al-khlifeh

Balard

Jarquín‐Díaz

et al. 2019

Preprint

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Species of Eimeria (Apicomplexa:Coccidia) differ in the timing of lifecycle progression and resulting infections vary in host immune reactions and pathology they induce. Eimeria infections in house mice are used as models for basic immunology and the most commonly used isolates have been passaged in laboratory mice for over 50 years. We questioned in how far such isolates are still representative for infections in natural systems.In the current study, we address this question by comparing the "laboratory isolate" E. falciformis BayerHaberkorn1970 with a novel, wild derived isolate E. falciformis Brandenburg88, and contrast this with another novel wild derived isolate, E. ferrisi Brandenburg64. We compare parasite lifecycle progression. We relate this to immune cell infiltration at the site of infection (in the caecum) and cytokine gene expression in the spleen as a measure of host immune response. We assess host weight loss as a measure of pathogenicity.A species-specific slower parasite lifecyle progression and higher pathogenicity are observed for E. falciformis vs. E. ferrisi. Host cytokines, in contrast, are expressed at significantly higher level in the 1 spleen of mice infected with the E. falciformis laboratory isolate than in both wild derived isolates, irrespective of the species. Differences in histopathology are observable between all three isolates: The E. falciformis BayerHaberkorn1970 laboratory isolate induces the strongest inflammation and cellular infiltration (with lymphocytes, plasma cells and eosinophilic granulocytes) followed by the wild derived E. falciformis Brandenburg88 isolate. E. ferrisi Brandenburg64 is inducing milder histological changes than both E. falciformis isolates.It can be speculated that the serial passaging of E. falciformis BayerHaberkorn1970 has resulted in evolutionary divergence rendering this isolate more virulent in NMRI mice. Caution is needed when findings from experimental infection with laboratory strains should be integrated with observations in natural systems.Highlights  E. ferrisi has a shorter pre-patency than wild-derived and laboratory isolates of E. falciformis. E. ferrisi is less virulent than both E. falciformis isolates and the timing of maximal oocyst shedding relative to host weight loss differs. The laboratory strain of E. falciformis induces stronger cytokine expression in the spleen than both wild derived strains of E. falciformis and E. ferrisi. The laboratory strain of E. falciformis induces stronger tissue infiltration of immune cells than the wild-derived strain. E. ferrisi infections are associated with the lowest infiltration.

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Section: Discussionsupporting

confidence: 94%

Section: Introductionmentioning

confidence: 99%

Eimeria falciformisBayerHaberkorn1970 and novel wild derived isolates from house mice: differences in parasite lifecycle, pathogenicity and host immune reactions

Al-khlifeh

Balard

Jarquín‐Díaz

et al. 2019

Preprint

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“…For instance, infection of mice with the roundworm Trichuris muris (a model of the human intestinal disease trichuriasis) induces IDO1 in goblet cells of the caecum of immune-deficient SCID (severe combined immunodeficiency) mice and studies with 1-MT provided evidence that IDO1 lowers the turnover rate of colonic epithelial cells, allowing the parasite to persist at the base of the caecal crypts [509]. Eimeria falciformis, which infects mouse intestinal epithelial cells, also takes advantage of IDO1 expression within the host; infection with this parasite induces IDO1 in the caecal epithelium, resulting in the formation of xanthurenic acid that is necessary for normal E. falciformis development [510]. In contrast, other Kyn pathway metabolites can suppress parasite function in vitro, e.g.…”

Section: Parasitesmentioning

confidence: 99%

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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“…The sequences of human and mouse IDO-2 show a similarity of approximately 43% to human and mouse IDO-1, respectively, which results in distinct substrate ranges and kinetic activities, different selectivities toward some inhibitors, and distinct expression patterns with regard to tissues and stimuli, which make a complete functional redundancy of IDO-1 and IDO-2 unlikely (13-16). While IDO-1 is encoded only by the genomes of mammals, IDO-2 can also be found in lower vertebrates (14).IDO-1 is not constitutively expressed but requires stimulation by host-and pathogen-derived inflammatory molecules such as proinflammatory cytokines (gamma interferon [IFN-␥], tumor necrosis factor [TNF]) and Toll-like receptor ligands (17), a regulation that functions as part of an immune response to pathological conditions such as protozoan infections (9,18,19). High levels of expression of IDO-1 lead to Trp depletion and increased levels of downstream neuroactive kynurenine metabolites (20).…”

mentioning

confidence: 99%

“…IDO-1 is not constitutively expressed but requires stimulation by host-and pathogen-derived inflammatory molecules such as proinflammatory cytokines (gamma interferon [IFN-␥], tumor necrosis factor [TNF]) and Toll-like receptor ligands (17), a regulation that functions as part of an immune response to pathological conditions such as protozoan infections (9,18,19). High levels of expression of IDO-1 lead to Trp depletion and increased levels of downstream neuroactive kynurenine metabolites (20).…”

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

Cited by 25 publications

References 50 publications

Eimeria falciformisBayerHaberkorn1970 and novel wild derived isolates from house mice: differences in parasite lifecycle, pathogenicity and host immune reactions

Eimeria falciformisBayerHaberkorn1970 and novel wild derived isolates from house mice: differences in parasite lifecycle, pathogenicity and host immune reactions

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

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

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