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.

Public Health Relevance

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.

Agency
National Institute of Health (NIH)
Institute
National Institute of Allergy and Infectious Diseases (NIAID)
Type
Research Project (R01)
Project #
2R01AI052733-06A1
Application #
7621215
Study Section
AIDS-associated Opportunistic Infections and Cancer Study Section (AOIC)
Program Officer
Duncan, Rory A
Project Start
2002-07-01
Project End
2014-06-30
Budget Start
2009-07-01
Budget End
2010-06-30
Support Year
6
Fiscal Year
2009
Total Cost
$478,446
Indirect Cost
Name
Albert Einstein College of Medicine
Department
Microbiology/Immun/Virology
Type
Schools of Medicine
DUNS #
110521739
City
Bronx
State
NY
Country
United States
Zip Code
10461
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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:
De Leon-Rodriguez, Carlos M; Fu, Man Shun; Çorbali, M Osman et al. (2018) The Capsule of Cryptococcus neoformans Modulates Phagosomal pH through Its Acid-Base Properties. mSphere 3:
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Martinez, Luis R; Boucaud, Dwayne W; Casadevall, Arturo et al. (2018) Factors Contributing to the Success of NIH-Designated Underrepresented Minorities in Academic and Nonacademic Research Positions. CBE Life Sci Educ 17:ar32
Almeida-Paes, Rodrigo; Almeida-Silva, Fernando; Pinto, Gabriela Costa Maia et al. (2018) L-tyrosine induces the production of a pyomelanin-like pigment by the parasitic yeast-form of Histoplasma capsulatum. Med Mycol 56:506-509
Vij, Raghav; Cordero, Radames J B; Casadevall, Arturo (2018) The Buoyancy of Cryptococcus neoformans Is Affected by Capsule Size. mSphere 3:
Rizzo, Juliana; Colombo, Ana C; Zamith-Miranda, Daniel et al. (2018) The putative flippase Apt1 is required for intracellular membrane architecture and biosynthesis of polysaccharide and lipids in Cryptococcus neoformans. Biochim Biophys Acta Mol Cell Res 1865:532-541

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