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.
|Jung, Eric H; Meyers, David J; Bosch, Jürgen et al. (2018) Novel Antifungal Compounds Discovered in Medicines for Malaria Venture's Malaria Box. mSphere 3:|
|Chatterjee, Subhasish; Prados-Rosales, Rafael; Tan, Sindy et al. (2018) The melanization road more traveled by: Precursor substrate effects on melanin synthesis in cell-free and fungal cell systems. J Biol Chem 293:20157-20168|
|Goldman, David L; Nieves, Edward; Nakouzi, Antonio et al. (2018) Serum-Mediated Cleavage of Bacillus anthracis Protective Antigen Is a Two-Step Process That Involves a Serum Carboxypeptidase. mSphere 3:|
|Casadevall, Arturo; Pirofski, Liise-Anne (2018) What Is a Host? Attributes of Individual Susceptibility. Infect Immun 86:|
|Perez-Dulzaides, Ricardo; Camacho, Emma; Cordero, Radames J B et al. (2018) Cell-wall dyes interfere with Cryptococcus neoformans melanin deposition. Microbiology 164:1012-1022|
|Fu, Man Shun; Casadevall, Arturo (2018) Divalent Metal Cations Potentiate the Predatory Capacity of Amoeba for Cryptococcus neoformans. Appl Environ Microbiol 84:|
|Casadevall, Arturo (2018) Fungal Diseases in the 21st Century: The Near and Far Horizons. Pathog Immun 3:183-196|
|De Leon-Rodriguez, Carlos M; Rossi, Diego C P; Fu, Man Shun et al. (2018) The Outcome of the Cryptococcus neoformans-Macrophage Interaction Depends on Phagolysosomal Membrane Integrity. J Immunol 201:583-603|
|Nosanchuk, J D; Jeyakumar, A; Ray, A et al. (2018) Structure-function analysis and therapeutic efficacy of antibodies to fungal melanin for melanoma radioimmunotherapy. Sci Rep 8:5466|
|Walker, Louise; Sood, Prashant; Lenardon, Megan D et al. (2018) The Viscoelastic Properties of the Fungal Cell Wall Allow Traffic of AmBisome as Intact Liposome Vesicles. MBio 9:|
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