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Pharmacologic Induction of Epidermal Melanin and Protection Against Sunburn in a Humanized Mouse Model
Published on: September 7, 2013
Melanin as a potential cryptococcal defence against microbicidal proteins
T L Doering1, J D Nosanchuk, W K Roberts
1The Department of Pharmacology, Cornell University Medical College, New York, NY 10021, USA. tdoering@mail.med.cornell.edu
Abstract:
Cryptococcus neoformans is an important fungal pathogen that synthesizes melanin when grown in the presence of phenolic substrates. The ability of C. neoformans to produce melanin is associated with virulence, but the specific role of melanin in the pathogenesis of infection is not clear. In this study the ability of C. neoformans melanin to bind proteins and protect against microbicidal peptides was investigated. Melanin was shown to bind a variety of proteins of fungal and mammalian origin. Melanin-protein interactions were dependent on the pH of the solution and on the amount of protein and melanin present. Melanized cells were less susceptible to killing by three microbicidal peptides: a defensin, a protegrin, and a magainin. Incubation of the microbicidal peptides with melanin particles, followed by removal of the melanin, reduced or abolished fungicidal activity, demonstrating interactions between peptides and melanin. The ability of melanin to bind proteins and to protect against microbicidal peptides suggests a protective function for melanin, whereby it sequesters microbicidal peptides and abrogates their activity.
Insights
Cryptococcus neoformans melanin binds proteins and protects the fungus from microbicidal peptides. This suggests melanin plays a role in fungal virulence by neutralizing host defenses.
Area of Science:
- Medical Mycology
- Biochemistry
Background:
- Cryptococcus neoformans is a significant fungal pathogen.
- Melanin production in C. neoformans is linked to virulence, but its precise role is unknown.
Purpose of the Study:
- To investigate the protein-binding capacity of C. neoformans melanin.
- To determine if melanin protects against microbicidal peptides.
Main Methods:
- Studied melanin-protein interactions under varying pH and concentrations.
- Assessed the susceptibility of melanized C. neoformans cells to defensins, protegrins, and magainins.
- Investigated the effect of melanin on the fungicidal activity of microbicidal peptides.
Main Results:
- C. neoformans melanin binds diverse fungal and mammalian proteins in a pH- and concentration-dependent manner.
- Melanized cells exhibited reduced susceptibility to killing by three distinct microbicidal peptides.
- Pre-incubation of peptides with melanin particles diminished their fungicidal activity.
Conclusions:
- C. neoformans melanin sequesters microbicidal peptides, abrogating their activity.
- Melanin's ability to bind proteins and neutralize antimicrobial peptides suggests a protective role in fungal pathogenesis.
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