Disease Tolerance Mediated by Phosphorylated Indoleamine-2,3 Dioxygenase Confers Resistance to a Primary Fungal Pathogen.

Eliseu Frank De Araújo,Cláudia Feriotti,Tania Costa,Paolo Puccetti,Vera Lúcia Garcia Calich,Carmine Vacca,Flávio Vieira Loures,Luigina Romani

doi:10.3389/fimmu.2017.01522

Eliseu Frank De Araújo, Cláudia Feriotti + Show 6 more

Open Access

https://doi.org/10.3389/fimmu.2017.01522

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Abstract

Resistance to primary fungal pathogens is usually attributed to the proinflammatory mechanisms of immunity conferred by interferon-γ activation of phagocytes that control microbial growth, whereas susceptibility is attributed to anti-inflammatory responses that deactivate immunity. This study challenges this paradigm by demonstrating that resistance to a primary fungal pathogen such as Paracoccidiodes brasiliensis can be mediated by disease tolerance, a mechanism that preserves host fitness instead of pathogen clearance. Among the mechanisms of disease tolerance described, a crucial role has been ascribed to the enzyme indoleamine-2,3 dioxygenase (IDO) that concomitantly controls pathogen growth by limiting tryptophan availability and reduces tissue damage by decreasing the inflammatory process. Here, we demonstrated in a pulmonary model of paracoccidioidomycosis that IDO exerts a dual function depending on the resistant pattern of hosts. IDO activity is predominantly enzymatic and induced by IFN-γ signaling in the pulmonary dendritic cells (DCs) from infected susceptible (B10.A) mice, whereas phosphorylated IDO (pIDO) triggered by TGF-β activation of DCs functions as a signaling molecule in resistant mice. IFN-γ signaling activates the canonical pathway of NF-κB that promotes a proinflammatory phenotype in B10.A DCs that control fungal growth but ultimately suppress T cell responses. In contrast, in A/J DCs IDO promotes a tolerogenic phenotype that conditions a sustained synthesis of TGF-β and expansion of regulatory T cells that avoid excessive inflammation and tissue damage contributing to host fitness. Therefore, susceptibility is unexpectedly mediated by mechanisms of proinflammatory immunity that are usually associated with resistance, whereas genetic resistance is based on mechanisms of disease tolerance mediated by pIDO, a phenomenon never described in the protective immunity against primary fungal pathogens.

Highlights

Indolamine-2,3 dioxygenase (IDO) is an intracellular enzyme of crucial importance in the tryptophan catabolism acting along the kynurenine (Kyn) pathway [1, 2]
This signaling function is mediated by TGF-β signaling that promotes IDO phosphorylation that activates the non-canonical NF-κB pathway that triggers genes encoding IDO, TGF-β, IFNα, and IFN-β, that maintain the tolerogenic activity of murine plasmacytoid dendritic cells (DCs) [12]
Phosphate-buffered saline (PBS)-washed yeast cells were adjusted to 20 × 106 cells/mL based on hemocytometer counts

Summary

Introduction

Indolamine-2,3 dioxygenase (IDO) is an intracellular enzyme of crucial importance in the tryptophan (trp) catabolism acting along the kynurenine (Kyn) pathway [1, 2]. IDO has been recently described as an intracellular signaling molecule involved in the sustained tolerogenic activity of DCs. IDO has been recently described as an intracellular signaling molecule involved in the sustained tolerogenic activity of DCs This signaling function is mediated by TGF-β signaling that promotes IDO phosphorylation that activates the non-canonical NF-κB pathway that triggers genes encoding IDO, TGF-β, IFNα, and IFN-β, that maintain the tolerogenic activity of murine plasmacytoid DCs [12]. This likely accounts for the ability of IDO to favor microbial persistence and concomitant control of inflammation during chronic infections [13,14,15]. Through the aryl hydrocarbon receptor (AhR), IDO directs the conversion of naive CD4+ T cells into regulatory Foxp3+ T cells (Tregs) [13, 16, 17]

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