Melanin synthesis has been associated with virulence for a variety of microbial pathogens. However, little is known about either melanogenesis or the structure of melanin. The experimental system that Dr. Nosanchuk will study is that of Cryptococcus neoformans, a pathogenic fungus which causes life-threatening meningitis in 5-10 percent of patients with AIDS. This system has several unique advantages for the study of melanin and virulence, including the fact that melanized and non-melanized cells can be easily generated by simply growing the organism with or without a variety of phenoloxidase substrates. In addition, melanogenesis in C. neoformans is catalyzed by a single enzyme. Dr. Nosanchuk proposes a novel approach to the study of melanin and melanogenesis C. neoformans by applying the technology of phage display libraries to identify melanin-binding peptides that will comprise unique reagents for the study of melanin. Furthermore, murine monoclonal antibodies (mAbs) will be generated that bind melanin. Melanin-binding peptides and mAbs will be used to study melanization in vitro and in vivo. The objectives are to determine whether melanogenesis occurs in vivo and to obtain information on the structure of melanin.
Four specific aims are proposed: 1. To identify peptides which bind melanin; 2. To study the antibody response to melanin and generate melanin-binding mAbs; 3. To explore the structure of melanin using biochemistry, phage display peptide libraries and mAbs; and 4. To use peptides and mAbs to study C. neoformans melanogenesis in vivo and in vitro.

National Institute of Health (NIH)
National Institute of Allergy and Infectious Diseases (NIAID)
Clinical Investigator Award (CIA) (K08)
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Microbiology and Infectious Diseases B Subcommittee (MID)
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Duncan, Rory A
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Albert Einstein College of Medicine
Internal Medicine/Medicine
Schools of Medicine
United States
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Martinez, Luis R; Mihu, Mircea Radu; Han, George et al. (2010) The use of chitosan to damage Cryptococcus neoformans biofilms. Biomaterials 31:669-79
Sanchez-Merino, Victor; Farrow, Melissa A; Brewster, Frank et al. (2008) Identification and characterization of HIV-1 CD8+ T cell escape variants with impaired fitness. J Infect Dis 197:300-8
Dadachova, Ekaterina; Nosanchuk, Joshua D; Shi, Li et al. (2004) Dead cells in melanoma tumors provide abundant antigen for targeted delivery of ionizing radiation by a mAb to melanin. Proc Natl Acad Sci U S A 101:14865-70
van Duin, David; Cleare, Wendy; Zaragoza, Oscar et al. (2004) Effects of voriconazole on Cryptococcus neoformans. Antimicrob Agents Chemother 48:2014-20
Nosanchuk, Joshua D; Casadevall, Arturo (2003) The contribution of melanin to microbial pathogenesis. Cell Microbiol 5:203-23
Morris-Jones, Rachael; Youngchim, Sirida; Gomez, Beatriz L et al. (2003) Synthesis of melanin-like pigments by Sporothrix schenckii in vitro and during mammalian infection. Infect Immun 71:4026-33
Steenbergen, Judith N; Nosanchuk, Joshua D; Malliaris, Stephanie D et al. (2003) Cryptococcus neoformans virulence is enhanced after growth in the genetically malleable host Dictyostelium discoideum. Infect Immun 71:4862-72
Gomez, Beatriz L; Nosanchuk, Joshua D (2003) Melanin and fungi. Curr Opin Infect Dis 16:91-6
Nosanchuk, Joshua D; Casadevall, Arturo (2003) Budding of melanized Cryptococcus neoformans in the presence or absence of L-dopa. Microbiology 149:1945-51
Nosanchuk, Joshua Daniel (2002) Fungal myocarditis. Front Biosci 7:d1423-38

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