Research Article: Malassezia Fungi Are Specialized to Live on Skin and Associated with Dandruff, Eczema, and Other Skin Diseases

Date Published: June 21, 2012

Publisher: Public Library of Science

Author(s): Charles W. Saunders, Annika Scheynius, Joseph Heitman, William E. Goldman.


Partial Text

Malassezia is a monophyletic genus of fungi found on the skin of 7 billion humans and associated with a variety of conditions, including dandruff, atopic eczema (AE)/dermatitis, pityriasis versicolor, seborrheic dermatitis, and folliculitis ([1], [2]; Figure 1). In immunocompromised hosts Malassezia can also cause systemic infections. There are 14 currently recognized species of Malassezia, eight of which have been associated with humans, four of these commonly [3]. Malassezia spp. are Basidiomycetous fungi, as are most species of fungi readily seen on a walk through the forest. Among the Basidiomycota, only Malassezia and Cryptococcus are frequent human pathogens. However, their adaptations to humans are presumed to be independent: Malassezia’s closest relatives are plant pathogens: the smuts and rusts, whereas the closest relatives for Cryptococcus pathogenic species are fungal saprotrophs associated with trees and insects. We summarize here a cellular and molecular description of some interactions of Malassezia with humans and speculate on properties (release of allergen-containing nanovesicles, mating) that may be critical to Malassezia virulence.

A genome sequence of Malassezia globosa reveals as small a genome size as any free-living fungus, with only 4,285 genes and spanning just ∼9 Mb [4]. This small genome size may reflect adaptation to the organisms’ limited niche, the skin of warm-blooded vertebrates [5]. While many of the genes for biosynthetic enzymes are present, M. globosa is the only free-living fungus known to lack a fatty acid synthase gene [4]. With a plethora of lipase genes, M. globosa likely satisfies its lipid requirement by hydrolysis of sebum triglycerides. Within the genus, only Malassezia pachydermatis, isolated from dogs and other non-human animals [5], is known to grow in the absence of exogenous lipid [1]. It will be interesting to learn whether this atypical species contains a fatty acid synthase gene similar to that found in the close relative Ustilago maydis and whether the habitat requirements of M. pachydermatis are, as a consequence, less stringent by relieving the requirement for exogenous lipids. While it is possible to culture Malassezia species axenically under laboratory conditions by providing exogenous lipids that mimic those available on human skin, some species are still quite fastidious, suggesting in vitro culture conditions may not be optimized.

Strictly no, despite the similarity of habitat. Dermatophytes such as Trichophyton rubrum, the cause of athlete’s foot infections, colonize and infect the skin and nails. The dermatophytes are ascomycetous fungi that are related phylogenetically to the dimorphic fungal pathogens. By contrast, the Malassezia species are superficial commensals of the skin but can provoke inflammatory reactions resulting in symptomatic skin diseases (folliculitis, dandruff, eczema) in humans and other animals. Yet a third fungal pathogen of animal skin is Batrachochytrium dendrobatidis, a chytrid fungus found on frog skin and associated with amphibian population declines and even species extinction events throughout the world [6]. This chytrid fungus is from a basal group of fungi, quite phylogenetically divergent from either dermatophytes or Malassezia[7]. A fourth fungal pathogen of animal skin is Geomyces destructans, an ascomycete associated with white-nose syndrome and mortality of bats [8]. All four groups of fungi have been subject to whole genome analysis ([4], [9], [10];, and their comparisons may reveal convergent solutions to adapting to such a unique environment as animal skin.

Maybe! So far no sexual cycle has been observed for any of the 14 species of Malassezia. But they are phylogenetically related to the Ustilago genus of plant fungal pathogens, and these organisms are stimulated to complete their sexual cycle during infection of their plant hosts [11]. In turn, it is the U. maydis filamentous dikaryon produced by mating that is capable of infecting the host plant—the yeast form is not infectious. By analogy, the Malassezia species may complete their sexual cycle during growth on human skin. There is a precedent among fungi: skin was found to stimulate mating of Candida albicans[12]. As with U. maydis, mating may result in the production of novel Malassezia growth forms, such as hyphae, or differences in their secreted antigen repertoire. Based on whole genome analysis, a region corresponding to the mating type locus (MAT) has been identified for M. globosa, a species associated with dandruff [4]. One region encodes homeodomain transcription factors and the other a candidate pheromone and pheromone receptor, similar to other basidiomycete fungi, such as U. maydis. But interestingly, these two regions appear to be physically linked in M. globosa, which is more similar to the organization of the MAT locus of a related plant pathogen Ustilago hordei[13]. This suggests that if there is an extant sexual cycle for M. globosa that it is more likely to be bipolar with just two mating types, rather than tetrapolar with many mating types. Transitions from tetrapolar to bipolar mating configurations are common in the basidiomycetes, and may be the consequence of transitions from outbreeding to inbreeding as species specialize to a particular host niche [14]–[16]. The M. globosa genome also reveals other genes associated with sexual reproduction, such as those encoding key proteins required for meiosis [4]. Another indirect line of evidence that species in this genus may be sexual is the observation that certain lineages of Malassezia furfur appear to be hybrids, based on amplified fragment length polymorphism molecular analysis that reveals their genomes are a composite of two parental lineages [17]. These hybrids may have been produced by mating of isolates of opposite mating type. Next steps in the ongoing analysis of sexual potential will involve 1) population genetic tests for recombination as an indirect measure of sex, 2) direct tests of mating under laboratory conditions, 3) analysis of whether mating genes are expressed during fungal culture on skin, possibly leading to fungal sex occurring on our skin, resulting in virulence, and 4) characterization of the organization and allele diversity of the mating type locus.

Unlike its phylogenetically close relative, U. maydis (the causative agent of corn smut), M. globosa has a paucity of glycosyl hydrolases, suggesting it lacks the carbohydrate-degrading capacity found in plant pathogens. In contrast, M. globosa and a phylogenetically distant relative, the ascomycete human pathogen C. albicans, have a similar set of multicopy genes encoding secreted enzymes, including lipases and acid sphingomyelinases [4], [18]. C. albicans can survive in several body sites, including the skin where M. globosa is found. This set of secreted enzymes may enable these fungi to survive and even thrive on human skin. Within the M. globosa genome, extracellular lipases, acid sphingomyelinases, aspartyl proteases, and phospholipases are encoded by clusters of similar genes, suggesting recent gene duplication [19]. While some of these enzyme families are known to be involved in fungal pathogenesis, development of transformation and homologous recombination approaches will be necessary to test the roles of these enzymes. Are there any beneficial effects for the host to harbor these yeasts on the skin? This isn’t known, but many individuals have used anti-fungal treatment for decades or longer without problems. If the fungi do confer benefits, they are either modest or at sites other than the scalp.

The anti-fungal mechanism of action has recently been described for one commonly used anti-dandruff shampoo active ingredient, zinc pyrithione (ZPT). Based on the ionophore properties of pyrithione and the demonstrated increase in mammalian cell zinc levels upon ZPT treatment [30], it was expected that ZPT would act by delivering high intracellular zinc levels to inhibit fungal growth. With the use of Saccharomyces cerevisiae as a model yeast, ZPT was discovered instead to increase cellular copper levels, and genetics was used to demonstrate the biological activity of the elevated copper [31]. As is the case with copper-mediated growth inhibition in bacteria [32], [33], iron-sulfur clusters are the targets of ZPT. The role of copper in ZPT-mediated growth inhibition was also found with M. globosa, but the iron-sulfur theme was not tested due to experimental challenges with Malassezia. If these principles apply to the scalp, then the zinc from ZPT must be replaced by a scalp source of copper, either from the natural disintegration of skin cells or immune cells, which have been recently shown to exploit copper to control microbes [34].

The study of host–pathogen interactions is more straightforward with skin pathogens than with systemic pathogens, as the pathogen is more easily studied in vivo. Malassezia are a ubiquitous component of the human skin microbiome and are associated with a myriad of skin problems, including dandruff in billions of people [37]. Malassezia are rarely found in places other than on animal skin, where they are such a common constituent of the flora that many (or possibly even all) warm-blooded animals harbor Malassezia on their skin. With the use of modern genomic and systems biology tools, we are poised to gain new insights in the interaction between humans and those eukaryotes with which we are most intimately associated, leading to perspectives on the duality of our symbiotic and antagonistic relationship.