Abstract

INTRODUCTION: Paracoccidioides brasiliensis is a pathogenic fungus restricted to Latin America and its natural route of infection is the inhalation of fungal particles. In PCM, the regulatory mechanisms mediated by innate and cellular immunity are still unclear. Indoleamine-2,3-dioxygenase (IDO) is an IFN-gamma induced enzyme which catalyses the tryptophan metabolism along the kynurenine pathway. It is known that IDO can control host-pathogen interaction by inhibiting the proliferation of intracellular microorganisms due to tryptophan starvation and by its immunosuppressive effect on T cell immunity. The aim of our work was to investigate in vivo the role of IDO in the immunoprotection of resistant (A/J) and susceptible (B10.A) mice against P.brasiliensis infection. METHODOLOGY: We worked with susceptible (B10.A) and resistant (AJ) mice using control and 1-methyl-DL-tryptophan (1MT, an IDO inhibitor)-treated mice. Control and 1MT-treated B10.A and A/J mice were infected i.t. with one million yeasts and analyzed at weeks 2 and 8 of infection. We analyzed the parameters of influence of treatment with 1MT in IDO mRNA expression; CFU counts; NO production; levels of kynurenine and cytokines; characterization of subpopulations of lymphocytes present in the lungs and frequency of CD4+CD25+FoxP3+ T cells and apoptosis in B10.A and A/J mice at the 2nd and 8th week of Pb infection. RESULTS: Early in infection of susceptible mice, IDO was shown to reduce fungal loads and to decrease the number and activation of inflammatory CD4+ and CD8+ T cells that migrate to the lungs. In resistant mice, IDO controls early fungal loads, but exerts a suppressive effect on T cell immunity only at week 8 post infection. In both mouse strains, IDO-mediated immunosuppression was associated with increased expansion of CD4+CD25+FoxP3+Treg cells and increased lymphocyte apoptosis. This is the first report showing the immunoregulatory effect of IDO in pulmonary PCM. CONCLUSION: In resistant and susceptible mice this enzyme exerts its dual role by diminishing fungal burdens but also suppressing T cell immunity due to its stimulatory effect on the expansion of regulatory T cells. ਀匀甀瀀瀀漀爀琀攀搀 戀礀 䘀䄀倀䔀匀倀