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Indoleamine 2,3-dioxygenase controls fungal loads and immunity in Paracoccidioidomicosis but is more important to susceptible than resistant hosts.

Araújo EF, Loures FV, Bazan SB, Feriotti C, Pina A, Schanoski AS, Costa TA, Calich VL - PLoS Negl Trop Dis (2014)

Bottom Line: Similar results were observed in the pulmonary infection.The early IDO inhibition resulted in increased differentiation of dendritic and Th17 cells, accompanied by reduced responses of Th1 and Treg cells.In fact, only in the susceptible background IDO inhibition resulted in uncontrolled tissue pathology and mortality rates.

View Article: PubMed Central - PubMed

Affiliation: Departamento de Imunologia, Instituto de Ciências Biomédicas, Universidade de São Paulo, São Paulo, São Paulo, Brazil.

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.

No MeSH data available.


Related in: MedlinePlus

1MT treatment increases fungal loads, tissue pathology and mortality rates of susceptible but not resistant mice to P. brasiliensis infection.Photomicrographs of lungs from 1MT treated and untreated A/J (A) and B10.A (B) mice at week 8 after infection with 1×106P. brasiliensis yeast cells obtained from groups of 5–6 mice. For panels: A and B, HE-stained, magnification ×10, Grocott-stained, magnification ×10. (C) Morphometric analysis of lung lesions of 1MT treated and untreated B10.A and A/J mice at week 8 post-infection (n = 5–6). (D) At weeks 2, 8 and 26 after infection, the presence of viable yeasts was determined in the liver of 1MT treated and untreated B10.A and A/J mice (n = 5–6). (E, F) Survival times of 1MT treated or untreated A/J and B10.A mice (9–10 mice per group) infected with 1×106P. brasiliensis yeasts were determined for a period of 250 days. The results are representative of two independent experiments (**p<0.01; ***p<0.001).
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pntd-0003330-g004: 1MT treatment increases fungal loads, tissue pathology and mortality rates of susceptible but not resistant mice to P. brasiliensis infection.Photomicrographs of lungs from 1MT treated and untreated A/J (A) and B10.A (B) mice at week 8 after infection with 1×106P. brasiliensis yeast cells obtained from groups of 5–6 mice. For panels: A and B, HE-stained, magnification ×10, Grocott-stained, magnification ×10. (C) Morphometric analysis of lung lesions of 1MT treated and untreated B10.A and A/J mice at week 8 post-infection (n = 5–6). (D) At weeks 2, 8 and 26 after infection, the presence of viable yeasts was determined in the liver of 1MT treated and untreated B10.A and A/J mice (n = 5–6). (E, F) Survival times of 1MT treated or untreated A/J and B10.A mice (9–10 mice per group) infected with 1×106P. brasiliensis yeasts were determined for a period of 250 days. The results are representative of two independent experiments (**p<0.01; ***p<0.001).

Mentions: The histopathology of lungs at week 8 of infection showed that control and 1MT treated A/J mice displayed reduced numbers of small, well-defined granulomas. The numbers of fungi were low, and sometimes absent from the lesions (Figure 4A). Compared with A/J mice, control B10.A mice exhibited higher numbers of large granulomas containing large amounts of fungi that affected larger areas of lungs. Furthermore, in comparison with untreated controls 1MT treated B10.A mice showed more severe lesions, composed of isolated or confluent granulomas containing a large number of budding yeast cells, involving extensive areas of lung parenchyma (Figure 4B). The total area of lesions was quantified in histological sections and shown in Figure 4C. At week 8, the lesion areas of 1MT treated B10.A mice were significantly larger than those of B10.A control mice. Whilst the lesion areas from A/J mice were smaller and showed no difference upon treatment, the histopathological studies demonstrated that administration of 1MT to susceptible mice resulted in increased fungal burdens that evolved with enhanced tissue inflammation. Further, as dissemination and control of fungal growth in the liver appear to be an important marker of the regressive and progressive infections of A/J and B10.A mice [40], [45], the fungal burden in the liver was determined. The results of CFU assays showed a significant increase in the number of viable yeasts in the1MT treated B10.A mice when compared with control mice, at weeks 8 and 26 after infection. Again, no differences in the fungal loads of A/J mice, treated or not with 1MT, were observed (Figure 4D). To further assess the influence of 1MT treatment on the disease outcome, mortality of treated and untreated P.brasiliensis infected A/J and B10.A mice was registered daily after infection with 1×106 yeast cells. 1MT treatment led to higher mortality of susceptible mice compared with control B10.A mice whereas no significant differences were observed in A/J mice, where 50% of control and 80% of 1MT treated resistant mice were still alive after 250 days of infection (Figure 4E, 4F).


Indoleamine 2,3-dioxygenase controls fungal loads and immunity in Paracoccidioidomicosis but is more important to susceptible than resistant hosts.

Araújo EF, Loures FV, Bazan SB, Feriotti C, Pina A, Schanoski AS, Costa TA, Calich VL - PLoS Negl Trop Dis (2014)

1MT treatment increases fungal loads, tissue pathology and mortality rates of susceptible but not resistant mice to P. brasiliensis infection.Photomicrographs of lungs from 1MT treated and untreated A/J (A) and B10.A (B) mice at week 8 after infection with 1×106P. brasiliensis yeast cells obtained from groups of 5–6 mice. For panels: A and B, HE-stained, magnification ×10, Grocott-stained, magnification ×10. (C) Morphometric analysis of lung lesions of 1MT treated and untreated B10.A and A/J mice at week 8 post-infection (n = 5–6). (D) At weeks 2, 8 and 26 after infection, the presence of viable yeasts was determined in the liver of 1MT treated and untreated B10.A and A/J mice (n = 5–6). (E, F) Survival times of 1MT treated or untreated A/J and B10.A mice (9–10 mice per group) infected with 1×106P. brasiliensis yeasts were determined for a period of 250 days. The results are representative of two independent experiments (**p<0.01; ***p<0.001).
© Copyright Policy
Related In: Results  -  Collection

License
Show All Figures
getmorefigures.php?uid=PMC4238999&req=5

pntd-0003330-g004: 1MT treatment increases fungal loads, tissue pathology and mortality rates of susceptible but not resistant mice to P. brasiliensis infection.Photomicrographs of lungs from 1MT treated and untreated A/J (A) and B10.A (B) mice at week 8 after infection with 1×106P. brasiliensis yeast cells obtained from groups of 5–6 mice. For panels: A and B, HE-stained, magnification ×10, Grocott-stained, magnification ×10. (C) Morphometric analysis of lung lesions of 1MT treated and untreated B10.A and A/J mice at week 8 post-infection (n = 5–6). (D) At weeks 2, 8 and 26 after infection, the presence of viable yeasts was determined in the liver of 1MT treated and untreated B10.A and A/J mice (n = 5–6). (E, F) Survival times of 1MT treated or untreated A/J and B10.A mice (9–10 mice per group) infected with 1×106P. brasiliensis yeasts were determined for a period of 250 days. The results are representative of two independent experiments (**p<0.01; ***p<0.001).
Mentions: The histopathology of lungs at week 8 of infection showed that control and 1MT treated A/J mice displayed reduced numbers of small, well-defined granulomas. The numbers of fungi were low, and sometimes absent from the lesions (Figure 4A). Compared with A/J mice, control B10.A mice exhibited higher numbers of large granulomas containing large amounts of fungi that affected larger areas of lungs. Furthermore, in comparison with untreated controls 1MT treated B10.A mice showed more severe lesions, composed of isolated or confluent granulomas containing a large number of budding yeast cells, involving extensive areas of lung parenchyma (Figure 4B). The total area of lesions was quantified in histological sections and shown in Figure 4C. At week 8, the lesion areas of 1MT treated B10.A mice were significantly larger than those of B10.A control mice. Whilst the lesion areas from A/J mice were smaller and showed no difference upon treatment, the histopathological studies demonstrated that administration of 1MT to susceptible mice resulted in increased fungal burdens that evolved with enhanced tissue inflammation. Further, as dissemination and control of fungal growth in the liver appear to be an important marker of the regressive and progressive infections of A/J and B10.A mice [40], [45], the fungal burden in the liver was determined. The results of CFU assays showed a significant increase in the number of viable yeasts in the1MT treated B10.A mice when compared with control mice, at weeks 8 and 26 after infection. Again, no differences in the fungal loads of A/J mice, treated or not with 1MT, were observed (Figure 4D). To further assess the influence of 1MT treatment on the disease outcome, mortality of treated and untreated P.brasiliensis infected A/J and B10.A mice was registered daily after infection with 1×106 yeast cells. 1MT treatment led to higher mortality of susceptible mice compared with control B10.A mice whereas no significant differences were observed in A/J mice, where 50% of control and 80% of 1MT treated resistant mice were still alive after 250 days of infection (Figure 4E, 4F).

Bottom Line: Similar results were observed in the pulmonary infection.The early IDO inhibition resulted in increased differentiation of dendritic and Th17 cells, accompanied by reduced responses of Th1 and Treg cells.In fact, only in the susceptible background IDO inhibition resulted in uncontrolled tissue pathology and mortality rates.

View Article: PubMed Central - PubMed

Affiliation: Departamento de Imunologia, Instituto de Ciências Biomédicas, Universidade de São Paulo, São Paulo, São Paulo, Brazil.

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.

No MeSH data available.


Related in: MedlinePlus