Abstract

Paracoccidioidomycosis (PCM), caused by the Paracoccidioides species, is a systemic disease endemic in several Latin American countries, mainly in Brazil, Colombia, Argentina, and Venezuela. Current treatment approaches are challenging as they require prolonged durations of antifungal drugs that have potential toxicities, and despite antifungals, relapses are common. Hence, new therapeutic approaches, such as vaccines, are being investigated. The therapeutic vaccine consisting of peptide P10 associated with lipid cationic DODAB (P10+DODAB) is effective in murine models of PCM. However, the specific immune mechanisms required for the protective response has not been fully elucidated. The present work aims at evaluating the participation of neutrophils in the immune response induced by P10+DODAB. We found that the vaccine reduced both the influx of pulmonary neutrophils and the fungal load in comparison to infected animals that did not receive this treatment. The parenchymal architecture of the lungs of P10+DODAB-treated animals was largely preserved with only a few granulomas present, and tissue cytokine analysis showed a Th1 cytokine profile with augmented levels of IL-12, IFN-γ and TNF-α, and low levels of IL-4. When neutrophils were depleted 24 h prior to each treatment, the effectiveness of the P10+DODAB vaccine was completely lost as the fungal burdens remained high and histological examination showed a marked inflammation and fungal dissemination with a dysregulated cytokine response. In conclusion, these findings indicate that neutrophils are vital to ensure the triggering of an effective immune response to P10+DODAB.

Highlights

  • Paracoccidioidomycosis (PCM) is a systemic mycosis that most frequently occurs in individuals in Brazil, Colombia, Venezuela, and Argentina [1]

  • The association of a known Th1-epitope harboring peptide (P10) from a P. brasiliensis gp43 molecule with a cationic lipid (DODAB) significantly reduced the pulmonary fungal load in mice infected with P. brasiliensis (Figure 1A)

  • We investigated the correlation between vaccine treatment, fungal load, and the presence of neutrophils in situ

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Summary

Introduction

Paracoccidioidomycosis (PCM) is a systemic mycosis that most frequently occurs in individuals in Brazil, Colombia, Venezuela, and Argentina [1]. Imported cases occur in other areas in the Americas as well as in Europe and Asia. The disease is due to the thermally dimorphic fungi of the Paracoccidioides genus, represented by two main species: P. brasiliensis and P. lutzii [2,3,4]. More recently, three other species were suggested: P. restrepiensis, P. venezuelensis, and P. americana [5]. Durations of treatment are long (frequently ~2 years) and relapses are common [6].

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