Paracoccidioidomycosis: reduction in fungal load and abrogation of delayed-type hypersensitivity anergy in susceptible inbred mice submitted to therapy with trimethoprim-sulfamethoxazole

Abstract

Isogenic mouse strains have previously been characterized as susceptible or resistant to Paracoccidioides brasiliensis infection; the former presented anergy in delayed-type hypersensitivity reactions (DTH) and progressive disease with high numbers of colony-forming units (CFU), while the later presented preserved DTH responses and control of the infectious process. Here, we studied whether susceptible mice infected with P. brasiliensis and treated with the antifungal drug trimethoprim-sulfamethoxazole (SXT) had their behavior pattern altered to the one observed in infected resistant mice. Therapy with either 30 or 150 mg SXT day⁻¹ kg⁻¹, instituted 24 h after infection, elicited more adequate DTH responses than those of non-treated mice, and also diminished the number of viable fungi in the spleen and lungs, but not in epiploo and liver, indicating a partial control of the infectious process. This phenomenon was confirmed by histopathological analyses, in which the spleen was found to be the organ in which differences between the treated and non-treated groups were most remarkable. In control non-treated mice, the spleen parenchyma showed multiple granulomatous foci presenting giant cells, plasmocytes and many yeasts of P. brasiliensis with well-preserved morphology and abundant budding, whereas SXT-treated mice, independently of the dosage used, had no granulomas within the parenchyma and only few capsular lesions, mainly composed of pseudoxantomatous macrophages. Treatment with 150 mg day⁻¹ kg⁻¹ (the dose considered to evoke best responses in CFU assays when therapy was instituted 24 h after infection), initiated at different times after infection, did not led to sustained DTH reactions, but provided an effective control of the disease when therapy began until the 15^th day post infection, as showed by CFU assays. We conclude that reversal from the susceptible to the resistant pattern in experimental paracoccidioidomycosis can occur, but only when therapy with an adequate SXT dosage is instituted at a very initial phase of the infection. These protocols may constitute a model for further investigations concerning responses during antifungal therapy.