Melanin pigments have been associated with virulence for most opportunistic fungal pathogens that cause life-threatening diseases in immunocompromised patients, including those with AIDS. Melanins contribute to virulence by increasing the fitness of the microbe in the host through a combination of reduced susceptibility to host immune mechanisms and subversion of the immune response. In addition, melanins reduce the susceptibility of fungi to polyene and echinocandin type antifungal agents and thus represent an important component of acquired drug resistance. Given the importance of melanin in virulence and drug resistance, the mechanisms that govern melanin synthesis and assembly in cell walls are potentially important targets for drug discovery. Recently, cell wall melanization was associated with increased fungal cell growth effects after exposure to gamma irradiation suggesting a novel role for this enigmatic pigment in energy transduction. This application proposes to continue our studies of the biology of fungal melanin by dissecting the process of melanization in the human pathogenic fungus Cryptococcus neoformans. This organism is a major pathogen for patients with AIDS and provides a unique system for the study of melanin biology because it melanizes only in the presence of an exogenous substrate and has an extensive genetic toolbox. The requirement for exogenous substrates in melanization provides a unique opportunity for studying melanin structure by using isotopic metabolic labeling and nuclear magnetic resonance spectroscopy. The goal of this research program is to further our understanding of melanin biology, function, and structure in pathogenic fungi.
Three specific aims are proposed: 1) To establish that melanization in C. neoformans is vesicle-associated;2) To establish the relationship between extracellular vesicles, melanosomes, and virulence;3) To investigate the molecular events of C. neoformans melanin biosynthesis.
This project is relevant to the mission of the NIH because studies of melanin can lead to new therapies for the treatment of fungal diseases. Furthermore, the research is also relevant to human diseases of pigmented tissues such as melanoma. In this regard, a monoclonal antibody to fungal melanin made as part of this research program is already in clinical evaluation for the therapy of melanoma.
|Stukes, Sabriya A; Cohen, Hillel W; Casadevall, Arturo (2014) Temporal kinetics and quantitative analysis of Cryptococcus neoformans nonlytic exocytosis. Infect Immun 82:2059-67|
|Brown, Lisa; Kessler, Anne; Cabezas-Sanchez, Pablo et al. (2014) Extracellular vesicles produced by the Gram-positive bacterium Bacillus subtilis are disrupted by the lipopeptide surfactin. Mol Microbiol 93:183-98|
|Stukes, Sabriya; Casadevall, Arturo (2014) Visualizing non-lytic exocytosis of Cryptococcus neoformans from macrophages using digital light microscopy. J Vis Exp :e52084|
|Navais, Roberto; Méndez, Jessica; Pérez-Pascual, David et al. (2014) The yrpAB operon of Yersinia ruckeri encoding two putative U32 peptidases is involved in virulence and induced under microaerobic conditions. Virulence 5:619-24|
|Albuquerque, Priscila C; Fonseca, Fernanda L; Dutra, Fabianno F et al. (2014) Cryptococcus neoformans glucuronoxylomannan fractions of different molecular masses are functionally distinct. Future Microbiol 9:147-61|
|Figueiredo-Carvalho, Maria Helena Galdino; dos Santos, Fábio B; Nosanchuk, Joshua D et al. (2014) L-Dihydroxyphenylalanine induces melanin production by members of the genus Trichosporon. FEMS Yeast Res 14:988-91|
|Rivera, Johanna; Morgenstern, Alfred; Bruchertseifer, Frank et al. (2014) Microbicidal power of alpha radiation in sterilizing germinating Bacillus anthracis spores. Antimicrob Agents Chemother 58:1813-5|
|Chatterjee, Subhasish; Prados-Rosales, Rafael; Tan, Sindy et al. (2014) Demonstration of a common indole-based aromatic core in natural and synthetic eumelanins by solid-state NMR. Org Biomol Chem 12:6730-6|
|Wolf, Julie M; Casadevall, Arturo (2014) Challenges posed by extracellular vesicles from eukaryotic microbes. Curr Opin Microbiol 22:73-8|
|Kaewmalakul, Jutikul; Nosanchuk, Joshua D; Vanittanakom, Nongnuch et al. (2014) Melanization and morphological effects on antifungal susceptibility of Penicillium marneffei. Antonie Van Leeuwenhoek 106:1011-20|
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