Targeting the P10 Peptide in Maturing Dendritic Cells via the DEC205 Receptor In Vivo: A New Therapeutic Strategy against Paracoccidioidomycosis

Paracoccidioidomycosis (PCM) is a systemic mycosis caused by Paracoccidioides brasiliensis, a thermally dimorphic fungus, which is the most frequent endemic systemic mycosis in many Latin American countries, where similar to 10 million people are believed to be infected. In Brazil, it is ranked as the tenth most common cause of death among chronic infectious diseases. Hence, vaccines are in development to combat this insidious pathogen. It is likely that effective vaccines will need to elicit strong T cell-mediated immune responses composed of IFN gamma secreting CD4(+) helper and CD8(+) cytolytic T lymphocytes. To induce such responses, it would be valuable to harness the dendritic cell (DC) system of antigen-presenting cells. To assess the potential of targeting P10, which is a peptide derived from gp43 secreted by the fungus, directly to DCs, we cloned the P10 sequence in fusion with a monoclonal antibody to the DEC205 receptor, an endocytic receptor that is abundant on DCs in lymphoid tissues. We verified that a single injection of the aDEC/P10 antibody caused DCs to produce a large amount of IFN?. Administration of the chimeric antibody to mice resulted in a significant increase in the levels of IFN-? and IL-4 in lung tissue relative to control animals. In therapeutic assays, mice pretreated with aDEC/P10 had significantly lower fungal burdens compared to control infected mice, and the architecture of the pulmonary tissues of aDEC/P10 chimera-treated mice was largely normal. Altogether, the results obtained so far indicate that targeting P10 through a aDEC/P10 chimeric antibody in the presence of polyriboinosinic: polyribocytidylic acid is a promising strategy in vaccination and therapeutic protocols to combat PCM.

Automated summary

Paracoccidioidomycosis (PCM) is a systemic mycosis caused by Paracoccidioides brasiliensis, a common endemic fungus in Latin American countries. Vaccines targeting strong T cell-mediated immune responses are being developed. The P10 peptide derived from the fungus has shown promise in inducing immune responses when targeted to dendritic cells (DC) with a monoclonal antibody to the DEC205 receptor. In experiments with mice, treatment with the aDEC/P10 chimeric antibody resulted in increased IFN-γ and IL-4 levels, reduced fungal burdens, and normal lung tissue architecture. This strategy shows potential for vaccination and therapy against PCM.