Melanin: Structure, Function, and Biosynthesis in Cryptococcus

There is an extensive body of evidence from several laboratories that establishes a role for melanization in virulence, providing a fascinating example of how a microorganism can utilize a ubiquitous pigment to undermine host defense mechanisms. Melanin-deficient mutant strains generated by UV-irradiation are avirulent in murine models of cryptococcal infection. The majority of Cryptococcus neoformans melanin is produced by Lac1, although a second laccase enzyme, Lac2, adjacent to LAC1 in the genome exists. Various microscopy techniques were used to develop the melanin model, including atomic force and scanning electron microscopy to examine the surface structure of melanin, transmission electron microscopy (TEM) to study cross sections of melanin, and nuclear magnetic resonance (NMR) cryoporometry to investigate the porosity of melanin. In the environment, melanin is thought to protect C. neoformans from various stresses including enzymatic degradation, radiation (UV, solar, gamma), and heavy metals (silver nitrate) while providing thermotolerance and structural integrity to withstand osmotic challenges. Melanin-binding drugs may be useful as therapeutics against C. neoformans infection. In fact, administration of melanin-binding monoclonal antibodies (MAbs) prolongs the survival of mice in a lethal intravenous infection model. In this study, the fungal burdens of collected brains and lungs of infected mice were taken 7 days after infection, and mice administered MAbs to melanin had significantly lower fungal burdens than control mice administered irrelevant immunoglobulin. Early studies that linked melanin to C. neoformans virulence used classical genetic techniques to generate mutants through nonspecific mutagenesis to identify yeast cells deficient in melanin production.