Cryptococcus neoformans melanization incorporates multiple catecholamines to produce polytypic melanin


Melanins have attracted considerable interest as putative virulence factors in fungi, and in the last 10 years increasing attention has been directed to the study of melanization in human pathogenic fungi. Some of the recognized human pathogens that form melanin precursors by the polyketide pathway include Aspergillus nidulans, A. niger, A. fumigatus, Alternaria alternata, Cladosporium carrionii, Exophiala dermatitidis, Exophiala jeanselmei, Fonsecae compacta, F. pedrososi, Hendersonulla toruloidii, Phaeoannellomyces werneckii, Phialophora richardsiae, and P. verrucosa. In contrast, Cryptococcus neoformans cannot make melanin without exogenous substrate, and the type of pigment synthesized varies depending on the chemical structure of the substrate added to the media. Melanization has been associated with fungal virulence as well as protection of C. neoformans against harsh environmental conditions, such as ultraviolet radiation, extremes of temperature, oxygen and nitrogen free radicals. Scientists believe that melanin could serve as a selective target for drug development against C. neoformans.

To have a better understanding of the factors influencing the melanin production in C. neoformans, Rosanna Baker, and Professor Arturo Casadevall from Johns Hopkins University together with Christine Chrissian, Professor Ruth Stark from The City College of New York analyzed the effects of various catecholamines found in animal brain tissue on melanization. The researchers used Solid-state nuclear magnetic resonance techniques to track the process of melanin synthesis in C. neoformans. To better understand the melanization process during an infection, they created a mixture of catecholamines which represented the human brain microenvironment. The original research article is now published in the Journal of Biological Chemistry.

To investigate the importance of melanin in the survival of C. neoformans, the authors explored the potential of natural melanin to protect against the harmful effects of free radicals generated by the body’s own cells. An in-house oxidative system was used to treat non-melanized and melanized KN99 cells. The presence of melanization precursors in the cells significantly increased the number of cells that survived exposure to harmful effects of oxidative stress. The research team showed that the synthesis of melanin was made simultaneously with the addition of multiple catecholamines, which suggests that the fungi were polytypic in nature. Moreover, the resulting melanin was able to protect the fungi against both ultraviolet light and oxidants. They also demonstrated that the amount of melanin produced during an infection depends on the composition of the catecholamines in the tissue. It also suggested that the use of a precursor chemical known as dopamine could allow the fungi to produce a similar pigment.

Melanization in C. neoformans has provided an excellent model system to study the mechanisms by which microbial melanins promote virulence in the brain. The study will facilitate factors to be considered in the design of future susceptibility testing methods and drug development. The results of the new study provide new insights into the melanization that are relevant to brain and will help understand the role of melanin in cryptococcal meningoencephalitis pathogenesis.

Cryptococcus neoformans melanization incorporates multiple catecholamines to produce polytypic melanin - Medicine Innovates

About the author

Arturo Casadevall, MD, PhD, is a Bloomberg Distinguished Professor and Alfred and Jill Summer Chair of the Molecular Microbiology and Immunology at Johns Hopkins School of Public Health. He received his M.D. and Ph.D. degrees from New York University. He completed his internship and residency in internal medicine at Bellevue Hospital in New York and completed subspecialty training in infectious diseases at the Albert Einstein College of Medicine. The author of over 900 papers, books and chapters, his major research interests are in fungal pathogenesis and the mechanisms of antibody action. He is editor-in-chief of mBio, Deputy Editor of the Journal of Clinical Investigation and serves on several editorial boards. He has served on the National Science Board for Biosecurity and the National Commission on Forensic Science. He is currently chair of the Board of Governors of the American Academy of Microbiology, the honorific arm of the American Society for Microbiology. He has received numerous honors including election to the American Society for Clinical Investigation, American Academy of Physicians, American Academy of Microbiology, Fellow of the American Academy for the Advancement of Science, American Academy of Arts and Sciences, AABB 2021 President’s Award and the National Academy of Medicine.

About the author

Rosanna Baker, MSc, is a Research Associate in the Department of Molecular Microbiology and Immunology at the Johns Hopkins Bloomberg School of Public Health in Baltimore, Maryland. Her current research is focused on the virulence mechanisms of the opportunistic human pathogen, Cryptococcus neoformans. Ms. Baker was born and raised in Nova Scotia, Canada where she attended Dalhousie University as a Canada Scholar, before continuing her education at the University of Alberta as a graduate scholar of the Alberta Heritage Foundation for Medical Research. Ms. Baker conducted scientific research in several renowned institutes, including the MRC Laboratory of Molecular Biology in Cambridge, England and the Center for Neurological Diseases at Harvard Medical School before joining the faculty of the Johns Hopkins University. Her work spanning the disciplines of enzymology, structural biology, biophysics, and cell biology has been published in 18 peer-reviewed journals.


Baker RP, Chrissian C, Stark RE, Casadevall A. Cryptococcus neoformans melanization incorporates multiple catecholamines to produce polytypic melanin. J Biol Chem. 2022 Jan;298(1):101519. doi: 10.1016/j.jbc.2021.101519.