Peptide-Pulsed Dendritic Cell Vaccination Confers Protection Response Against Paracoccidioides lutzii in an...

Paracoccidioidomycosis (PCM) is a systemic fungal infection that remains an important public health concern in Brazil. Although the disease is generally responsive to antifungal treatment, the duration of therapy is prolonged and relapses may occur, highlighting the need for alternative strategies and preventative approaches. We have demonstrated that peptide-based vaccines combined with dendritic cell (DC)-based platforms represent a promising strategy to modulate host immune responses against PCM. In this study, we evaluated the immunomodulatory potential of synthetic peptides derived from Paracoccidioides lutzii antigens, including the well-characterized P10 peptide from P. brasiliensis, integrating in silico prediction, in vitro validation, and in vivo models. In silico prediction utilized available databases and tools to characterize the peptides properties. Lead candidates were synthesized and evaluated for cytotoxicity, demonstrating low toxicity in tested conditions. Stimulation of bone marrow-derived dendritic cells (bmDCs) with the peptides promoted a progressive maturation profile, characterized by increased expression of MHC-II and co-stimulatory molecules, particularly following longer pulsing times. Immunization of mice with peptide-pulsed bmDCs significantly reduced pulmonary fungal burden in infected animals and treatment was associated with lower inflammation and the presence of more compact granulomas, indicating reduced tissue damage. These protective effects correlated with a beneficial cytokine profile, including decreased IL-4, IL-10 and TGF-β levels and increased production of TNF-α, IL-12p70, IL-17A and IL-23, suggesting a shift from a regulatory/Th2 environment toward a protective Th1/Th17 response. Notably, this work is the first to demonstrate that P. brasiliensis P10 could confer protection in a P. lutzii infection model. Collectively, these findings highlight the potential of peptide-pulsed DC vaccination to reshape pulmonary immunity and improve disease control in PCM.