Indoleamine 2,3-Dioxygenase Activity During Acute Toxoplasmosis and the Suppressed T Cell Proliferation in Mice.

Christoph-Martin Ufermann,Irmgard Förster,Silvia Kathrin Eller,Ursula Regina Sorg,Sevgi Can Cengiz,Andreas Domröse,Walter Däubener,Timo Babel,Anne Tersteegen,Katrin Spekker-Bosker

doi:10.3389/fcimb.2019.00184

Christoph-Martin Ufermann, Irmgard Förster + Show 8 more

Open Access

https://doi.org/10.3389/fcimb.2019.00184

Copy DOI

Abstract

Toxoplasma gondii (T. gondii) is an obligate intracellular parasite and belongs to the phylum Apicomplexa. T. gondii is of medical and veterinary importance, because T. gondii causes the parasitic disease toxoplasmosis. In human cells, the interferon-gamma inducible indoleamine 2,3-dioxygenase 1 (IDO1) is an antimicrobial effector mechanism that degrades tryptophan to kynurenine and thus limits pathogen proliferation in vitro. Furthermore, IDO is described to have immunosuppressive properties, e.g., regulatory T cell differentiation and T cell suppression in humans and mice. However, there is only little known about the role of IDO1 in mice during acute toxoplasmosis. To shed further light on the role of mIDO1 in vivo, we have used a specifically adjusted experimental model. Therein, we infected mIDO1-deficient (IDO−/−) C57BL/6 mice and appropriate wild-type (WT) control mice with a high dose of T. gondii ME49 tachyozoites (type II strain) via the intraperitoneal route and compared the phenotype of IDO−/− and WT mice during acute toxoplasmosis. During murine T. gondii infection, we found mIDO1 mRNA and mIDO1 protein, as well as mIDO1-mediated tryptophan degradation in lungs of WT mice. IDO−/− mice show no tryptophan degradation in the lung during infection. Even though T. gondii is tryptophan auxotroph and rapidly replicates during acute infection, the parasite load was similar in IDO−/− mice compared to WT mice 7 days post-infection. IDO1 is described to have immunosuppressive properties, and since T cell suppression is observed during acute toxoplasmosis, we analyzed the possible involvement of mIDO1. Here, we did not find differences in the intensity of ex vivo mitogen stimulated T cell proliferation between WT and IDO−/− mice. Concomitant nitric oxide synthase inhibition and interleukin-2 supplementation increased the T cell proliferation from both genotypes drastically, but not completely. In sum, we analyzed the involvement of mIDO1 during acute murine toxoplasmosis in our specifically adjusted experimental model and found a definite mIDO1 induction. Nevertheless, mIDO1 seems to be functional redundant as an antiparasitic defense mechanism during acute toxoplasmosis in mice. Furthermore, we suggest that the systemic T cell suppression observed during acute toxoplasmosis is influenced by nitric oxide activity and IL-2 deprivation.

Highlights

The apicomplexan parasite Toxoplasma gondii (T. gondii) is, due to the fact that it can infect most warmblooded animals, considered to be the most successful parasite worldwide
The group of Munn and coworkers found an important function for IDO in the development of immune tolerance in allogeneic pregnancy in mice and described a profound immunosuppression mediated by IDO-positive human macrophages (Munn et al, 1998, 1999). They described the tryptophan depletion as a possible reason for the inhibited T cell proliferation (Munn et al, 1998, 1999); we suggest that this local reduction of tryptophan could cause a local antimicrobial environment
Murine mIDO2 was measured as well to exclude mIDO2 as a responsible candidate for results shown further on. mIDO2 is only marginally increased during T. gondii infection in a few infected mice and there is no significant difference between WT and IDO−/− mice (Figure 1B)

Summary

Introduction

The apicomplexan parasite Toxoplasma gondii (T. gondii) is, due to the fact that it can infect most warmblooded animals, considered to be the most successful parasite worldwide. A primary T. gondii infection in humans is usually asymptomatic, but can cause congenital toxoplasmosis and can lead to fatal consequences for the fetus or newborn. T. gondii establishes a chronic infection and will persist lifelong in the host. Reactivation of a chronic T. gondii infection in humans—e.g., during immunosuppression—results in cerebral toxoplasmosis in most cases (Schlüter et al, 2014). A recent study by Wilking et al (2016) showed that T. gondii infection, while depending on demographic factors, is highly prevalent in Germany; about 55% of the representative cohort was seropositive for T. gondii. Defense mechanisms directed against T. gondii are intensively studied. Extensive data were obtained analyzing murine toxoplasmosis since the mouse model is the preferred animal model to study toxoplasmosis in vivo (Gazzinelli et al, 2014; Yarovinsky, 2014; Sasai et al, 2018)

Methods

Results

Conclusion