Abstract
Paracoccidioidomycosis (PCM), a common chronic mycosis in Latin America, is a granulomatous systemic disease caused by the thermo-dimorphic fungus Paracoccidioides brasiliensis. The glycoprotein gp43 is the main antigen target of P. brasiliensis and a 15-mer internal peptide (QTLIAIHTLAIRYAN), known as P10, defines a major CD4+-specific T cell epitope. Previous results have indicated that, besides having a preventive role in conventional immunizations prior to challenge with the fungus, protective anti-fungal effects can be induced in P. brasiliensis-infected mice treated with P10 administered with complete Freund’s adjuvant (CFA). The peptide elicits an IFN-γ-dependent Th1 immune response and is the main candidate for effective immunotherapy of patients with PCM, as an adjunctive approach to conventional chemotherapy. In the present study we tested the therapeutic effects of P10 combined with different adjuvants [aluminum hydroxide, CFA, flagellin, and the cationic lipid dioctadecyl-dimethylammonium bromide (DODAB)] in BALB/c mice previously infected with the P. brasiliensis Pb18 strain. Significant reductions in the number of colony forming units of the fungus were detected in lungs of mice immunized with P10 associated with the different adjuvants 52 days after infection. Mice treated with DODAB and P10, followed by mice treated with P10 and flagellin, showed the most prominent effects as demonstrated by the lowest numbers of viable yeast cells as well as reductions in granuloma formation and fibrosis. Concomitantly, secretion of IFN-γ and TNF-α, in contrast to interleukin (IL)-4 and IL-10, was enhanced in the lungs of mice immunized with P10 in combination with the tested adjuvants, with the best results observed in mice treated with P10 and DODAB. In conclusion, the present results demonstrate that the co-administration of the synthetic P10 peptide with several adjuvants, particularly DODAB, have significant therapeutic effects in experimental PCM.
Highlights
Paracoccidioidomycosis (PCM) is a systemic mycosis that typically starts as a granulomatous pulmonary disease subsequent to the inhalation of conidia of the dimorphic fungus Paracoccidioides brasiliensis
COLONY FORMING UNITS IN INFECTED BALB/c MICE IMMUNIZED WITH PEPTIDE 10 (P10) After 30 days of infection, immunizations were initiated with three weekly doses of P10 with or without the different adjuvants
Lungs of mice immunized with P10 along with each of the different adjuvants had a significantly reduced number of colony forming unit (CFU) compared to controls (Figure 1)
Summary
Paracoccidioidomycosis (PCM) is a systemic mycosis that typically starts as a granulomatous pulmonary disease subsequent to the inhalation of conidia of the dimorphic fungus Paracoccidioides brasiliensis. When it is not diagnosed and treated properly, P. brasiliensis yeast cells can spread rapidly to lymph nodes, tegument, spleen, liver, and lymphoid organs of the digestive tract (Shikanai-Yasuda et al, 2006). A specific T-CD4+ cell epitope was mapped to a 15-amino acid sequence designated P10, which is recognized by T cells from mice infected with P. brasiliensis. P10 immunized animals produced greater amounts of IFN-γ and interleukin (IL)-12. These mice had significantly reduced damage to lung tissue. We have begun to investigate the efficacy of different adjuvants co-administered with www.frontiersin.org
Sign-in/Register to view highlights & summary 
Published Version (
Free)
Talk to us
Join us for a 30 min session where you can share your feedback and ask us any queries you have
Schedule a call