Indoleamine 2,3-Dioxygenase Controls Fungal Loads and Immunity in Paracoccidioidomicosis but is More Important to Susceptible than Resistant Hosts

Abstract

Background

Paracoccidioidomycosis, 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 Findings

In 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/Significance

Our 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.

Author Summary

Immunoprotection to paracoccidiodomycosis, a systemic mycosis endemic in Latin America, is mediated by T cell immunity whereas immunosuppression characterizes the severe forms of the disease. Indoleamine 2,3-dioxygenase (IDO), an enzyme mainly induced by IFN-γ, catabolizes tryptophan along the kynurenines pathway. Tryptophan deficiency has been associated with reduced pathogen growth, while elevated levels of kynurenines with suppressed immune responses. In this study, the role of IDO in pulmonary paracoccidioidomycosis was investigated using resistant and susceptible mice. In both mouse strains, IDO blockade by 1-methyl tryptophan resulted in inefficient fungal clearance accompanied by enhanced T cell immunity. Despite these equivalent biological effects, only in susceptible mice IDO inhibition caused progressive fungal growth and tissue pathology resulting in increased mortality. Our findings demonstrate for the first time that IDO exert a yet unexplored immunoregulatory role in pulmonary paracoccidioidomycosis that can be particularly important in the severe cases of the disease.