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.
|Cordero, Radames J B; Liedke, Susie Coutinho; de S AraÃºjo, Glauber R et al. (2016) Enhanced virulence of Histoplasma capsulatum through transfer and surface incorporation of glycans from Cryptococcus neoformans during co-infection. Sci Rep 6:21765|
|Stukes, Sabriya; Coelho, Carolina; Rivera, Johanna et al. (2016) The Membrane Phospholipid Binding Protein Annexin A2 Promotes Phagocytosis and Nonlytic Exocytosis of Cryptococcus neoformans and Impacts Survival in Fungal Infection. J Immunol 197:1252-61|
|DeLeon-Rodriguez, Carlos M; Casadevall, Arturo (2016) Cryptococcus neoformans: Tripping on Acid in the Phagolysosome. Front Microbiol 7:164|
|Nimrichter, Leonardo; de Souza, Marcio M; Del Poeta, Maurizio et al. (2016) Extracellular Vesicle-Associated Transitory Cell Wall Components and Their Impact on the Interaction of Fungi with Host Cells. Front Microbiol 7:1034|
|Prados-Rosales, Rafael; CarreÃ±o, Leandro J; Weinrick, Brian et al. (2016) The Type of Growth Medium Affects the Presence of a Mycobacterial Capsule and Is Associated With Differences in Protective Efficacy of BCG Vaccination Against Mycobacterium tuberculosis. J Infect Dis 214:426-37|
|Janda, Alena; Eryilmaz, Ertan; Nakouzi, Antonio et al. (2015) Variable Region Identical IgA and IgE to Cryptococcus neoformans Capsular Polysaccharide Manifest Specificity Differences. J Biol Chem 290:12090-100|
|Pirofski, Liise-anne; Casadevall, Arturo (2015) What is infectiveness and how is it involved in infection and immunity? BMC Immunol 16:13|
|Brown, Lisa; Wolf, Julie M; Prados-Rosales, Rafael et al. (2015) Through the wall: extracellular vesicles in Gram-positive bacteria, mycobacteria and fungi. Nat Rev Microbiol 13:620-30|
|Freitas, Dayvison F S; Santos, Suelen S; Almeida-Paes, Rodrigo et al. (2015) Increase in virulence of Sporothrix brasiliensis over five years in a patient with chronic disseminated sporotrichosis. Virulence 6:112-20|
|Almeida, Fausto; Wolf, Julie M; Casadevall, Arturo (2015) Virulence-Associated Enzymes of Cryptococcus neoformans. Eukaryot Cell 14:1173-85|
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