About our research

Our research - a brief summary

What can you tell me about your subject of study, Wangiella dermatitidis?

What is phaeohyphomycosis?

In layman's terms, why is your research important?

Research Summary

     My laboratory uses the so-called black yeast Wangiella dermatitidis (also know as Exophiala dermatitidis) as a model to discover cell wall-related virulence factors among the more than 100 black fungi known to cause human disease. The importance of our studies relates to the knowledge that fungi blackened by the polymerization of dihydroxynaphthalene (DHN) into melanin (DHN-melanin) in their cell walls are among those most resistant to current strategies of antifungal chemotherapeutic intervention. Therefore, the discovery of critical, but vulnerable, steps leading to the synthesis of DHN-melanin and other cell wall components in our model should identify excellent potential targets for the design of antifungal therapeutic agents. These compounds should be useful not only for the treatment of infections caused by black fungi, but also other less resistant but more common species.

     Over the years, members of my research groups have carried out a variety of studies of Wangiella using techniques of cell biology, genetics, physiology and biochemistry aimed at establishing this fungus as a model. However, during the last decade, my group has mostly been engaged in cloning and studying genes and their encoded products, which are involved in its cell wall biosynthesis.  For this purpose,  we are using a variety of newly developed transformation, gene disruption, and gene expression strategies. The focus of these studies has been toward a molecular genetic analysis of the relevance of chitin and melanin biosynthesis to virulence, and of genes that affect the extent and location of their cell wall deposition. Although progress has been made in all these areas, most has involved the five chitin synthase (WdCHS) structural genes we have identified. Because chitin biosynthesis per se does not occur in vertebrates or mammals, the essential multiple processes leading to the chitin synthesis are considered to be important potential targets for drug development.

     Our results to date suggest that: i) no single chitin synthase (WdChsp: an enzyme that polymerize chitin) is required viability and growth of W. dermatitidis at 25^oC; ii) of its five chitin chitin synthases, WdChs5p  contributes most directly to virulence, probably because this isozyme is required for sustained growth at infection temperatures (37^oC); iii)  WdChs1p and WdChs2p also contribute to virulence, because at least one of these two isozymes is required with WdChs5 for viability at 37^oC; iv) WdChs3p likewise contributes to virulence with WdChs2p, because at least one of these two isozymes is required with WdChs5p for virulence in our mouse models. Currently we are attempting to discover the regulatory mechanisms that control the specific functions of these zymogenic enzymes, which allow them to contribute to virulence in association with melanin and in the different growth forms of Wangiella expressed in human tissues.

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What can you tell me about your subject of study, Wangiella dermatitidis?

Wangiella dermatitidis, also often called Exophiala dermatitidis,  is a so-called dematiaceous fungus that causes a variety of infections known collectively as "phaeohyphomycosis".   It is a species in the form-phylum Fungi Imperfecti (Deuteromycetes), which means it has no known sexual cycle, although a wealth of data strongly suggest it is a member of the fungal phylum Ascomycota.   What distinguishes it as dematiaceous is the black pigment (a type of melanin) that is in the cell walls of all its different cell types. Wangiella is also a polymorphic organism, which means that it exists in a variety of cell forms. These  include its most common yeast cell type and the less common "sclerotic" cell, moniliform hypha, true hypha, and conidium (spore) cell types.  It the laboratory it is grown mostly as a yeast in rich liquid medium, but can be induced to convert to other forms by modifying growth conditions.  

Wangiella is not readily found in the environments but has been isolated worldwide.  Although ubiquitous, it causes only relatively few mycoses (fungal diseases), Nontheless some reported cases have been very serious and have resulted in patient death.

In vivo phenotypes of Wangiella dermatitidis (L).                      Colony of Wangiella dermatitidis on rich medium (R).

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What is phaeohyphomycosis?

Phaeohyphomycosis is a term that was created in 1974 to include several  infections that  are caused by many but not all mycotic diseases caused by black fungi.    Phaeohyphomycosis can be superficial (on the surface of the skin, hair, or nails), cutaneous (involving the skin immediately below the outer epidermis), subcutaneous (involving fatty tissue, connective tissue, or muscle tissue), or systemic (involving the circulatory and/or lymphatic system).  The more serious life-threatening, systemic phaeohyphomycoses, mostly occurs with immunosuppressed individuals.  Although phaeohyphomycosis traditionally has been most associated with dermotrophic forms of disease, emerging systemic forms are being detected in increasing number.  For example, predisposing factors for systemic infections with W. dermatitidis include cystic fibrosis, lymphocytic leukemia, diabetes mellitus, bronchiectasis, rheumatoid arthritis and catherization.

For more information on the clinical aspect of this topic, see Matsumoto, T., Matsuda, T., McGinnis, M.R., and Ajello, L.  1992.  Clinical and mycological spectra of Wangiella dermatitidis infections.  Mycoses 36: 145-155.

Ungual phaeohyphomycosis (L),    Cutaneous phaeohyphomycosis (R). courtesy of Dr. Tadahiko Matsumoto, Dept. of Dermatology, Toshiba Hospital, 6-3-22 Higashi-oi, Shinagawa-ku, Tokyo 140, Japan

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Help! I'm not a scientist!  Can you translate any of this for me?

 Wangiella dermatitidis, the subject of this lab's research, is a black (melanized) fungus.   Fungi (the plural of fungus) are a kingdom of organisms that include your garden variety mushroom  (Agaricus brunnescens), baker's yeast (Saccharomyces cerevisiae),  the causative agents of athlete's foot (E. floccosum, T. mentagrophytes, and T. rubrum), the cause of yeast infections (Candida albicans),  the mold you might see growing on your bread or cheese (Rhizopus stolnifer), or the mold (Penicillium notatum) that produces the medicine used to combat an infection.   Most people are unaware of all the roles(both positive and negative)  that fungi play in our lives. 

Wangiella has been known to cause disease that can exhibit a wide variety of symptoms.  Although it can certainly be life-threatening, that in itself is not the only reason for researching this organism.  Fungi have many common attributes with "higher" life forms.   Many biochemical and molecular properties of cell growth and regulation are similar.  Thus, fungi like Wangiella can be used as models to investigate fungi and other life forms that are not as easily studied at biochemical and molecular levels.

Wangiella has been demonstrated to be a paradigm for mycotic infections caused by black fungi.  This means that it alone elicits all the broad varieties of disease manifestations in humans which are characteristic of those presented by any other melanized fungus..  Understanding the mechanisms that control the growth of these fungi will provide insights into their pathogenicity and virulence and may lead to improved treatments.

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