title: Melanin in the dimorphic fungal pathogen Paracoccidioides brasiliensis: effects on phagocytosis, intracellular resistance and drug susceptibility.
abstract: The fungal pathogen Paracoccidioides brasiliensis produces a melanin-like pigment in the presence of l-DOPA in vitro. We investigated whether melanization affected yeast uptake by alveolar and peritoneal macrophages, the intracellular resistance of fungal cells and their susceptibility to antifungal drugs. The interactions of melanized and nonmelanized P. brasiliensis with murine primary macrophages and J774.16 and MH-S macrophage-like cell lines were investigated. Melanized yeast cells were poorly phagocytosed by the cells even in the presence of complement. Melanization caused significant interference with the binding of cell wall components to lectin receptors on macrophages. Melanized cells were also more resistant than nonmelanized cells to the antifungal activity of murine macrophages. No difference in the susceptibilities of melanized and nonmelanized P. brasiliensis to antifungal drugs was observed using the minimum inhibitory concentration (MIC) method. However killing assays showed that melanization significantly reduced fungal susceptibility to amphotericin B and also protected against ketoconazole, fluconazole, itraconazole and sulfamethoxazole. The present results indicate that fungal melanin protects P. brasiliensis from phagocytosis and increases its resistance to antifungal drugs.
authors.affiliation: Department of Microbiology, Institute of Biomedical Sciences, University of São Paulo, Av. Prof. Lineu Prestes, 1374, 2 andar, São Paulo, SP 05508-900, Brazil.
authors.forename: Marcelo B
authors.initials: MB
authors.lastname: da Silva
authors.forename: Alexandre F
authors.initials: AF
authors.lastname: Marques
authors.forename: Josh D
authors.initials: JD
authors.lastname: Nosanchuk
authors.forename: Arturo
authors.initials: A
authors.lastname: Casadevall
authors.forename: Luiz R
authors.initials: LR
authors.lastname: Travassos
authors.forename: Carlos P
authors.initials: CP
authors.lastname: Taborda
mesh_terms: D000818:Animals; D000935:Antifungal Agents / Q000494:pharmacology*; D025141:Drug Resistance, Fungal / Q000502:physiology*; D042845:Laccase; D007980:Levodopa / Q000378:metabolism; D016676:Macrophages, Alveolar / Q000378:metabolism; D017737:Macrophages, Peritoneal / Q000378:metabolism; D008351:Mannans / Q000494:pharmacology; D008543:Melanins / Q000378:metabolism*; D051379:Mice; D008807:Mice, Inbred BALB C; D008826:Microbial Sensitivity Tests; D010228:Paracoccidioides / Q000166:cytology / Q000187:drug effects* / Q000235:genetics / Q000378:metabolism*; D010587:Phagocytosis
chemical_list: D000935:Antifungal Agents; D008351:Mannans; D008543:Melanins; D007980:Levodopa; D042845:Laccase