Abstract
Paracoccidioidomycosis, PCM, the major systemic mycosis in Latin America, is caused by the termally dimorphic fungus Paracoccidioides brasiliensis and requires extended periods of chemotherapy with a significant frequency of relapsing disease. The search for new alternatives of treatment is necessary. rPb27 is an antigenic protein from P. brasiliensis that already showed a significant protective activity as a vaccine for PCM in experimental models. The cDNA of rPb27 was subcloned into a pET-DEST 42 plasmid, expressed in E. coli with a his-tag and purified by affinity chromatography. Immunization with this recombinant protein and chemotherapy were used together in an attempt to improve treatment of PCM. For this, BALB/c mice were challenged with pathogenic P. brasiliensis strain and after immunized with rPb27, in the presence of Corynebacterium parvum and Al(OH)3, some groups were also treated with fluconazole. After 40 days of treatment, the combined drug/rPb27 administration controlled PCM in the liver and spleen, with long lasting protection, and largely preserved tissues structures of these organs. Additionally, in the lungs after 40 days of treatment there was a significant reduction in the fungal load and size of lesions. At the same time, the levels of TNF-α were higher than infected-only mice. Moreover, significant levels of anti-rPb27 specific IgG1, IgG2a and IgG2b isotypes were detected in the sera of mice immunized with rPb27 fluconazole treated or not. These results showed an additive protective effect of rPb27 immunization and chemotherapy, suggesting that an rPb27-based vaccine can be used to enhance PCM antifungal treatment.
Highlights
Paracoccidioidomycosis (PCM) is a systemic granulomatous disease caused by Paracoccidioides brasiliensis, a termally dimorphic fungus widespread in Latin America mainly affecting rural workers [1]
Cloning and sequencing of rPb27 DNA resulted in 773 bp comprising the entire rPb27 gene open reading frame and some nucleotides that were added by the plasmid
Organ colony-forming units (CFUs) from intratracheally infected BALB/c mice immunized with rPb27 and/or treated with fluconazole
Summary
Paracoccidioidomycosis (PCM) is a systemic granulomatous disease caused by Paracoccidioides brasiliensis, a termally dimorphic fungus widespread in Latin America mainly affecting rural workers [1]. The fatal acute PCM affects the reticule endothelial system, whereas the chronic PCM affects mainly the lung, which shows a granulomatous inflammation with an inefficient cellular immune response [1,3]. The conventional treatment of PCM is based on sulfonamides, amphotericin B and azole derivates. The introduction of azoles marked an advance in the treatment of fungal diseases, PCM among them. Imidazoles (ketoconazole) and triazoles (fluconazole, saperconazole, and itraconazole) have been extensively used for the treatment of PCM and have proven effective for clinical purposes, showing fewer side effects than amphotericin B [1]
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