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

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.

Tolerogenic Plasmacytoid Dendritic Cells Control Paracoccidioides brasiliensis Infection by Inducting Regulatory T Cells in an IDO-Dependent Manner

“…It is important to note that the main effect of IDO inhibition in the immunity of resistant and susceptible mice previously reported [30] is different from that here reported. In B10.A mice, the IDO activity is mainly mediated by IFN-γ, whereas in the resistant A/J mice IDO is mainly induced by TGF-β signaling [2, 30]. In addition, the early tolerogenic response developed by A/J mice is transitory and later counter balanced by a pro-inflammatory activity and prevalent NLRP3 activation resulting in a late Th1/Th17 immunity tightly regulated by Treg cells [57, 67].…”

“…This balance is fundamental to the coevolution of host immunity and commensal fungal infections that occur without excessive detrimental effects to both organisms [64, 66]. It is important to note that the main effect of IDO inhibition in the immunity of resistant and susceptible mice previously reported [30] is different from that here reported. In B10.A mice, the IDO activity is mainly mediated by IFN-γ, whereas in the resistant A/J mice IDO is mainly induced by TGF-β signaling [2, 30].…”

“…In addition, the production of IDO by pDCs has been linked to the proliferation and activation of resting Foxp3 + Treg cells [30, 31]. Our findings demonstrating a reduced frequency of Treg cells in pDC-depleted mice, led us to further investigate the participation of IDO in the tolerance mechanisms promoted by pDCs.…”

“…Our recent study showed that indolemine 2,3 dioxygenase control fungal burdens, and inflammatory reactions in pulmonary PCM [30]. In addition, the production of IDO by pDCs has been linked to the proliferation and activation of resting Foxp3 + Treg cells [30, 31].…”

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

“…Mouse strains that show differing susceptibility to P. brasiliensis infection nonetheless display similar extents of increased IDO1 expression within the lung [488]. Inhibition of IDO1 through 1-DL-MT treatment increased early fungal burden in the lung, promoted inflammation and inhibited Th1/Treg immunity, while increasing IL-17 production.…”