Georgios Gaitanis, Prokopios Magiatis, Markus Hantschke, Ioannis D. Bassukas, and Aristea Velegraki
In the last 15 years, the genus Malassezia has been a topic of intense basic research on taxonomy, physiology, biochemistry, ecology, immunology, and metabolomics. Currently, the genus encompasses 14 species. The 1996 revision of the genus resulted in seven accepted taxa: M. furfur, M. pachydermatis, M. sympodialis, M. globosa, M. obtusa, M. restricta, and M. slooffiae. In the last decade, seven new taxa isolated from healthy and lesional human and animal skin have been accepted: M. dermatis, M. japonica, M. yamatoensis, M. nana, M. caprae, M. equina, and M. cuniculi. However, forthcoming multidisciplinary research is expected to show the etiopathological relationships between these new species and skin diseases. Hitherto, basic and clinical research has established etiological links between Malassezia yeasts, pityriasis versicolor, and sepsis of neonates and immunocompromised individuals. Their role in aggravating seborrheic dermatitis, dandruff, folliculitis, and onychomycosis, though often supported by histopathological evidence and favorable antifungal therapeutic outcomes, remains under investigation. A close association between skin and Malassezia IgE binding allergens in atopic eczema has been shown, while laboratory data support a role in psoriasis exacerbations. Finally, metabolomic research resulted in the proposal of a hypothesis on the contribution of Malassezia-synthesized aryl hydrocarbon receptor (AhR) ligands to basal cell carcinoma through UV radiation-induced carcinogenesis.
Seborrheic dermatitis (synonym, seborrheic eczema) is a relapsing skin disease that shows a predilection for the so-called seborrheic areas of the skin, such as the scalp, eyebrows, paranasal folds, chest, back, axillae, and genitals, and is characterized by recurrent erythema and scaling. However, it should also be stressed that despite its designation, seborrhea is not present in seborrheic dermatitis. No widely accepted criteria regarding the diagnosis and grading of seborrheic dermatitis exist, and identification can constitute a clinical problem for psoriasis patients with facial involvement, a condition termed sebopsoriasis. Seborrheic dermatitis was initially described by Unna, and the association with Malassezia yeasts was accepted up to the middle of the 20th century, when the observed increased epidermal cell turnover gradually prompted researchers to characterize this condition as being intrinsic to the skin, analogous to psoriasis. The recognition of the role of Malassezia yeasts in seborrheic dermatitis pathogenesis was reappraised in the 1980s, when it was shown that the common denominator of the multiple treatment regimens used for seborrheic dermatitis was their antifungal activity.
The prevalence of seborrheic dermatitis is high, reaching 11.6% in a study from the United States, while dermatologists had diagnosed this condition in 2.6% of men and 3.0% of women in a relevant study. The disease is more common in certain populations, such as the elderly, and can be severe and therapy resistant in neuroleptic-induced Parkinsonism and HIV patients. The occasionally observed clinical resistance to azole drugs in some cases of seborrheic dermatitis could be attributed to variable genotypes of the recently described M. globosa azole-metabolizing CYP51 enzyme.
The prevalence of seborrheic dermatitis peaks when sebaceous gland activity is high, during the first 3 months of life (infantile seborrheic dermatitis) and during puberty, but also when sebum excretion is reduced after the age of 50 years. Seborrheic dermatitis flares are also observed in the fall, when the level of sebum production is decreased compared to that in summer. The flare of disease could be associated with altered population dynamics, which would be affected not only by variations in sebaceous gland activity but also by modifications in other nutrients supplied by sweat, such as essential amino acids like glycine and tryptophan. It has been shown in vitro that glycine stimulates the fast growth of M. furfur, and when this amino acid is exhausted, yeast cells employ tryptophan as a nitrogen source, increasing the production of indolic metabolites. Such cycles of population growth, bioactive indole production, and subsequent deprivation of nutrients could result in insufficiently masked antigens and ligands on the surface of the yeast cells, which would result in the activation of the immune system. One study showed that increased numbers of metabolically active cells during summer resulted in higher rates of isolation in culture medium than in fall, although the actual DNA loads were equal in both seasons. The difference in the rates of active versus stationary/dead yeasts cells would result in the differential regulation of the skin immune response.
Seborrheic dermatitis and Malassezia.Currently available data are not sufficient to define Malassezia virulence factors that lead to the appearance or exacerbation of seborrheic dermatitis. It should be noted that skin is the niche of Malassezia, and the interplay of the yeast with keratinocytes and immune cells determines the transformation of this commensal to a pathogen.
Environmental factors, such as UV radiation and antagonistic microorganisms, may constitute stress factors similarly for Malassezia yeasts and the skin. Thus, the ability of Malassezia to locally modify the immune response, in addition to host susceptibility and the production of secondary metabolites by the yeast, probably participates in eliciting and maintaining seborrheic dermatitis. Higher production rates of aryl hydrocarbon receptor (AhR) ligands in vitro by M. furfur have been associated with seborrheic dermatitis isolates. AhR is found in sebocytes, and its function is modified by epidermal growth factor receptor (EGFR). The latter probably has a seborrheic distribution, as antibodies or small molecules that block its function cause a folliculocentric eruption with a seborrheic distribution, and the interplay of these two receptors was proposed previously. Thus, an initial approach to understanding the participation of aryl hydrocarbon receptor in seborrheic dermatitis would be to study polymorphisms of the implicated downstream proteins in patients and healthy controls and associate them with the indole-producing capacity of Malassezia strains that are isolated from their skin.
Current evidence demonstrates that seborrheic dermatitis results from a nonspecific immune response to Malassezia yeasts. Unfortunately, very few experiments were performed after the identification of new Malassezia species, and this is reflected in the available data. Inflammatory markers recorded by immunocytochemistry of skin biopsy specimens from seborrheic dermatitis lesions show an increase in levels of inflammatory mediators (interleukin-1α [IL-1α], IL-1β, IL-2, IL-4, IL-6, IL-10, IL-12, gamma interferon [IFN-γ], and tumor necrosis factor alpha [TNF-α]) in the epidermis and around the follicles of diseased skin. These inflammatory markers are equivalent to those produced by Malassezia yeasts in experimental models. However, this increase did not differ statistically from levels in adjacent, healthy-looking skin and varied only from levels on the skin of healthy volunteers, suggesting an individual susceptibility to the development of seborrheic dermatitis. Furthermore, Malassezia yeasts demonstrated an ability to induce immune reactions, depending on the species, the culture growth phase, yeast cell viability, and the integrity of Malassezia cells. The 2 species that are commonly isolated from human skin (M. globosa and M. restricta) demonstrate distinct profiles of proinflammatory cytokine production from epidermal cells, with M. globosa stimulating the production of significantly more cytokines than M. restricta. However, the net effect of this cytokine synthesis, i.e., immune stimulation or tolerance, cannot be extracted from published data, as experimental conditions are not comparable. For example, even the use of different culture media could result in different compositions of the lipid layer that covers the cell wall of Malassezia, resulting in a variable modulation of the immune system. In a recent study, the levels of binding and activation of the C-type lectin Mincle caused by Malassezia yeasts were higher than those of other fungi. However, the growth of Malassezia yeasts in a medium with only olive oil as a lipid source would have resulted in an insufficient masking of mannose residues that could subsequently be recognized by Mincle.
Another virulence factor intrinsic to Malassezia yeasts that has been discussed in association with the pathogenesis of seborrheic dermatitis is the production of phospholipases and the response to β-endorphin. The increased level of production of phospholipase after β-endorphin stimulation has been shown only for pathogenic M. pachydermatis strains; however, there is evidence that this also applies to lipophilic Malassezia species, although to date, this has been reproducible in vitro only for M. furfur. However, sebum production is increased by β-endorphin, and the demonstration of a functional μ-opioid receptor in pathogenic and nonpathogenic M. pachydermatis strains has been shown. This points toward the existence of an equivalent sensory pathway in the lipophilic Malassezia species that could assist in the preparation of the yeast for a better utilization of sebaceous lipids. The aberrant production of Malassezia phospholipases on the skin could result in the removal of epidermal lipids, disruption of the epidermal barrier function, and the development of seborrheic dermatitis when sebum production is constitutionally decreased. Phospholipase production is a well-established virulence factor in Candida albicans, and the existence of environmental sensory G-protein-coupled receptors in fungi has been show. Mining of the sequenced genome of M. globosa would lead to the recognition and detection of relevant genes in Malassezia and their association with the pathogenetic potential of the respective strains.