Abstract
BackgroundParacoccidioidomycosis, a primary fungal infection restricted to Latin America, is acquired by inhalation of fungal particles. The immunoregulatory mechanisms that control the severe and mild forms of paracoccidioidomycosis are still unclear. Indoleamine 2,3-dioxygenase (IDO), an IFN-γ induced enzyme that catalyzes tryptophan metabolism, can control host-pathogen interaction by inhibiting pathogen growth, T cell immunity and tissue inflammation.Methodology/Principal FindingsIn this study, we investigated the role of IDO in pulmonary paracoccidioidomycosis of susceptible and resistant mice. IDO was blocked by 1-methyl-dl-tryptophan (1MT), and fungal infection studied in vitro and in vivo. Paracoccidioides brasiliensis infection was more severe in 1MT treated than untreated macrophages of resistant and susceptible mice, concurrently with decreased production of kynurenines and IDO mRNA. Similar results were observed in the pulmonary infection. Independent of the host genetic pattern, IDO inhibition reduced fungal clearance but enhanced T cell immunity. The early IDO inhibition resulted in increased differentiation of dendritic and Th17 cells, accompanied by reduced responses of Th1 and Treg cells. Despite these equivalent biological effects, only in susceptible mice the temporary IDO blockade caused sustained fungal growth, increased tissue pathology and mortality rates. In contrast, resistant mice were able to recover the transitory IDO blockade by the late control of fungal burdens without enhanced tissue pathology.Conclusions/SignificanceOur studies demonstrate for the first time that in pulmonary paracoccidioidomycosis, IDO is an important immunoregulatory enzyme that promotes fungal clearance and inhibits T cell immunity and inflammation, with prominent importance to susceptible hosts. In fact, only in the susceptible background IDO inhibition resulted in uncontrolled tissue pathology and mortality rates. Our findings open new perspectives to understand the immunopathology of paracoccidioidomycosis, and suggest that an insufficient IDO activity could be associated with the severe cases of human PCM characterized by inefficient fungal clearance and excessive inflammation.
Highlights
Indoleamine-2,3-dioxygenase (IDO) is the major and rate limiting cytosolic enzyme of tryptophan catabolism along the kynurenines pathway [1] and is expressed primarily in macrophages, epithelial and dendritic cells (DCs)
Some immunoregulatory pathways that are induced by the decreased levels of tryptophan could be linked with inhibition of mammalian target of rapamycyn signaling and activation of the amino acid sensitive general control nonderepressible 2 (GCN2) stress kinase pathway, that can cause cell cycle arrest, anergy and apoptosis of responding T cells [5,8,9]
We sought to investigate the effects of IDO inhibition in the interaction between macrophages from susceptible and resistant mice with P. brasiliensis
Summary
Indoleamine-2,3-dioxygenase (IDO) is the major and rate limiting cytosolic enzyme of tryptophan catabolism along the kynurenines pathway [1] and is expressed primarily in macrophages, epithelial and dendritic cells (DCs). The enzyme is induced by proinflammatory cytokines (e.g., IFN-c), Toll-like receptor ligands (e.g., lipopolysaccharide), and interactions between immune cells (e.g., the engagement of costimulatory molecules on antigen-presenting cells by cytotoxic T-lymphocyte antigen-4) [2,3,4,5]. Some immunoregulatory pathways that are induced by the decreased levels of tryptophan could be linked with inhibition of mammalian target of rapamycyn (mToR) signaling and activation of the amino acid sensitive general control nonderepressible 2 (GCN2) stress kinase pathway, that can cause cell cycle arrest, anergy and apoptosis of responding T cells [5,8,9]. Indoleamine 2,3-dioxygenase (IDO), an IFN-c induced enzyme that catalyzes tryptophan metabolism, can control host-pathogen interaction by inhibiting pathogen growth, T cell immunity and tissue inflammation
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