Cutaneous Malassezia: Commensal, Pathogen, or Protector?

Abstract

The skin microbial community is a multifunctional ecosystem aiding prevention of infections from transient pathogens, maintenance of host immune homeostasis, and skin health. A better understanding of the complex milieu of microbe-microbe and host-microbe interactions will be required to define the ecosystem's optimal function and enable rational design of microbiome targeted interventions. Malassezia, a fungal genus currently comprising 18 species and numerous functionally distinct strains, are lipid-dependent basidiomycetous yeasts and integral components of the skin microbiome. The high proportion of Malassezia in the skin microbiome makes understanding their role in healthy and diseased skin crucial to development of functional skin health knowledge and understanding of normal, healthy skin homeostasis. Over the last decade, new tools for Malassezia culture, detection, and genetic manipulation have revealed not only the ubiquity of Malassezia on skin but new pathogenic roles in seborrheic dermatitis, psoriasis, Crohn's disease, and pancreatic ductal carcinoma. Application of these tools continues to peel back the layers of Malassezia/skin interactions, including clear examples of pathogenicity, commensalism, and potential protective or beneficial activities creating mutualism. Our increased understanding of host- and microbe-specific interactions should lead to identification of key factors that maintain skin in a state of healthy mutualism or, in turn, initiate pathogenic changes. These approaches are leading toward development of new therapeutic targets and treatment options. This review discusses recent developments that have expanded our understanding of Malassezia's role in the skin microbiome, with a focus on its multiple roles in health and disease as commensal, pathogen, and protector.

Keywords: Malassezia; commensal; host and disease; immunity; multikingdom; mutualist; pathogen; skin.

Figure 1

Phylogenetic tree of all 18 currently accepted Malassezia species. Malassezia can be subdivided into subgroups A, B, and C based on Wu et al. PLoS Genetics 2015. Tree constructed from most current NCBI LSU data ( Table 1 ) using the MAFFT method to generate multi-align sequence (MSA), UPGMA (unweighted pair group method with arithmetic mean) for clustering, phylogenetic tree viewed using Newick viewer. MAFFT v6.864 is a multiple alignment program for amino acid or nucleotide sequences (Katoh et al., 2005). (http://www.trex.uqam.ca/index.php?action=mafft and http://mafft.cbrc.jp/alignment/software/). Known species of inhabitation and activities can be found in Table 1 . Arrows indicate hypothesized chromosome losses associated with development of new species (Sankaranarayanan et al., 2020). Dark blue box = nine chromosome ancestral lineage. Dark blue arrows, nine chromosome lineages. Light blue arrow predicted centromere loss to eight chromosomes. Pink arrow predicted centromere loss to seven chromosomes. Orange arrow unknown chromosome loss to six chromosomes. Yellow unknown event ()? resulting in loss to six chromosomes. (* = documented by centromere loss) (M. pachydermatis chromosome number postulated from complete genome assemblies, M. obtusa hypothesized based on PGFE karyotype) (Kiuchi et al., 1992; Boekhout et al., 1998; Kim et al., 2018).

Figure 2

Cross talk between skin and microbiota in healthy and diseased skin states (such as seborrheic dermatitis and atopic dermatitis). The skin and the immune system evolve together with resident microorganisms to establish commensal microbial relationships (for example, Malassezia in green). In the healthy state (A), skin maintains high microbial diversity when compared to active disease states in seborrheic dermatitis (SD) and atopic dermatitis (AD) as shown in (B, C). Keratinocytes sense microbial population through recognition of microbial pathogen-associated molecular patterns (PAMPs) motifs via their pattern recognition receptors (PRR’s), Leucine rich repeat (LRR’s) containing receptors and Toll-like receptors (TLR’s) as shown in (A). The binding of PAMPs to PRRs, LRRs and TLRs triggers innate immune responses, resulting in the secretion of antimicrobial peptides that can rapidly inactivate a diverse range of pathogenic microorganisms, including fungi, bacteria and parasites. The Langerhans cells interact with microbial antigens in the epidermis to detect barrier breach and maintain homeostasis (A). The skin tolerance is dependent on regulatory T cells, a subset of lymphocytes infiltrate skin, concomitant with hair follicle and skin microbial colonization in based on cytokines TGF-Beta and IL-10 (A). In SD, alterations in sebum content creates favorable conditions for expansion of Malassezia as the dominant species that may cause the disease (B). Increased Malassezia colonization initiates specific utilization of stratum corneum fatty acids that are converted into by-products such as oleic acid, arachidonic acid which irritates and causes inflammation in the skin. Irritants such as indole and Malassezin could increase keratinocyte (KC) proliferation and induce inflammation (B). Accumulation of histamine in the SD lesions is suggestive of mast cell degranulation (B). In AD there is increased pathogen colonization that causes probable decreased commensal microbial diversity and a defective skin barrier(C). Malasszeia and other pathogens could stimulate sub epidermal layers and releases antigens which are recognized by TLR2 receptors feedback to DC or T cell population which stimulates immune response The disrupted skin barrier allows microbial entry in to skin which probably increases cytokines IL-4, IL-10 and IL-13 levels. Circulating anti- Malassezia IgE has been reported in AD (C). The figure was created using Biorender.com.