Melanin is a pigment that performs a variety of functions and is found in the plant and animal kingdoms. In fungi melanin reinforces cell walls, shields against ultraviolet radiation as well as toxic metals, harnesses high energy electromagnetic radiation and contributes to virulence. Despite its importance, very little is known about the structure of melanin because it is insoluble and amorphous, making it difficult to analyze. In the previous funding period we described a new, melanin-based process for harnessing energy through the capture of radiation; we laid the foundation for a new melanoma therapy targeting melanin that is now in clinical trials; we demonstrated the remarkable ability of melanin to shield against radiation and provided a novel way to study the structure of melanin by solid-state NMR analysis; we discovered an extracellular vesicular transport in fungi (associated with the formation of a fungal melanosome). This research program renewal is focused on melanization in the human pathogenic fungus Cryptococcus neoformans, which is responsible for almost a million annual cases of meningitis worldwide, primarily in patients with AIDS. We will build on the achievements and tools of the previous funding period in order to focus on the fungal melanosome and the process of melanization.
Three Specific Aims are proposed: 1) To generate a molecular definition for the cargo in melanizing vesicle populations; 2) To investigate the mechanism by which the fungal melanosome interacts with the cell wall; 3) To investigate the molecular structure of C. neoformans melanin assemblies on their cell-wall scaffold. C. neoformans melanin is critical for virulence and it is also a potential target for therapeutic drug development. Agents that target melanin are attractive because they could be applied against a broad array of pathogenic fungi.

Public Health Relevance

Melanin is a complex pigment that is involved in numerous biological processes from protection against sunlight to energy harvest. Melanin also contributes to fungal virulence by undermining host defense mechanisms and melanized fungi are much less resistant to certain antifungal drugs. This proposal seeks to understand how melanin is made in an important human pathogenic fungus because this information is of fundamental importance for understanding fungal cell biology and can potentially lead to new therapies that target melanization pathways.

Agency
National Institute of Health (NIH)
Institute
National Institute of Allergy and Infectious Diseases (NIAID)
Type
Research Project (R01)
Project #
5R01AI052733-15
Application #
9416056
Study Section
AIDS-associated Opportunistic Infections and Cancer Study Section (AOIC)
Program Officer
Love, Dona
Project Start
2003-07-01
Project End
2020-01-31
Budget Start
2018-02-01
Budget End
2019-01-31
Support Year
15
Fiscal Year
2018
Total Cost
Indirect Cost
Name
Johns Hopkins University
Department
Microbiology/Immun/Virology
Type
Schools of Public Health
DUNS #
001910777
City
Baltimore
State
MD
Country
United States
Zip Code
21205
Cordero, Radames J B; Vij, Raghav; Casadevall, Arturo (2017) Microbial melanins for radioprotection and bioremediation. Microb Biotechnol 10:1186-1190
Cleare, Levi G; Zamith-Miranda, Daniel; Nosanchuk, Joshua D (2017) Heat Shock Proteins in Histoplasma and Paracoccidioides. Clin Vaccine Immunol 24:
Grossman, Nina T; Casadevall, Arturo (2017) Physiological Differences in Cryptococcus neoformans Strains In Vitro versus In Vivo and Their Effects on Antifungal Susceptibility. Antimicrob Agents Chemother 61:
Camacho, Emma; Chrissian, Christine; Cordero, Radames J B et al. (2017) N-acetylglucosamine affects Cryptococcus neoformans cell-wall composition and melanin architecture. Microbiology 163:1540-1556
Casadevall, Arturo (2017) The Pathogenic Potential of a Microbe. mSphere 2:
Almeida-Paes, Rodrigo; Almeida-Silva, Fernando; Pinto, Gabriela Costa Maia et al. (2017) L-tyrosine induces the production of a pyomelanin-like pigment by the parasitic yeast-form of Histoplasma capsulatum. Med Mycol :
Pirofski, Liise-Anne; Casadevall, Arturo (2017) Immune-Mediated Damage Completes the Parabola: Cryptococcus neoformans Pathogenesis Can Reflect the Outcome of a Weak or Strong Immune Response. MBio 8:
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
Prados-Rosales, Rafael; CarreƱo, 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
DeLeon-Rodriguez, Carlos M; Casadevall, Arturo (2016) Cryptococcus neoformans: Tripping on Acid in the Phagolysosome. Front Microbiol 7:164

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