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COMMENTARY

Woollard WJ, Pullabhatla V, Lorenc A, Patel VM, pathways preceding tumor formation in a mu- of yeasts within the basidiomycetes that
Butler RM, Bayega A, et al. Candidate driver rine model of T-cell lymphoma in skin. J Invest
is closely related to the smut plant
genes involved in genome maintenance and Dermatol 2011;131:1727e34.
DNA repair in Sezary syndrome. Blood pathogen Ustilago maydis and more
Yu H, Lee H, Herrmann A, Buettner R, Jove R.
2016;127:3387e97.
Revisiting STAT3 signalling in cancer: new and
distantly related to skin-infecting fungal
Wu X, Sells RE, Hwang ST. Upregulation of in- unexpected biological functions. Nat Rev species, such as Candida albicans
flammatory cytokines and oncogenic signal Cancer 2014;14:736e46. and the dermatophytes. The unique
Malassezia genus currently includes 17
species, of which M. globosa,
See related article on pg 1137 M. restricta, and M. sympodialis are
most commonly associated with
The Skin Commensal Yeast humans (Sparber and Leibund Gut-
Landmann, 2017). A common feature
Malassezia globosa Thwarts is the inability of Malassezia to
synthesize lipids due to the loss of the
Bacterial Biofilms to Benefit fatty acid synthase gene, and as a
consequence, these species mainly
colonize sebaceous skin. Comprehen-
the Host sive molecular and genetic research on
Malassezia has highlighted unique
Giuseppe Ianiri1, Joseph Heitman1 and Annika Scheynius2
features compared with other fungi,
Malassezia are abundant, lipid-dependent, commensal yeasts in the skin such as a reduction in genome size (as
microbiome that also have a pathogenic lifestyle associated with several com- small as approximately 7e9 Mbp) with
mon skin disorders. Malassezia genomes encode myriad lipases and proteases extensive loss of genes encoding hy-
thought to mediate lipid utilization and pathogenesis. Li et al. report the drolases and other enzymes involved
biochemical characterization of a unique secreted aspartyl protease produced in carbohydrate metabolism, and
by Malassezia globosa, MgSAP1, and demonstrate its active role in hindering concomitant expansion of genes
biofilm formation of the bacterium Staphylococcus aureus. Because biofilms are encoding secreted lipases and pro-
an established virulence attribute of S. aureus, this study reveals a potential teases thought to mediate lipid utiliza-
benefit to the host of the fungal aspartyl protease MgSAP1 and opens the door tion and play roles in pathogenesis
for the investigation of the roles of such molecules in microbial interactions and (Wu et al., 2015).
their possible effects on the host.
Is Malassezia a beneficial skin
Journal of Investigative Dermatology (2018) 138, 1026e1029. doi:10.1016/j.jid.2018.01.008
inhabitant?
Although Malassezia are commensal
inhabitants of the skin, they are asso-
ciated with several skin disorders,
Fungi of the genus Malassezia including pityriasis versicolor, dandruff,
A secreted aspartyl seborrheic dermatitis, atopic dermatitis
The skin of humans and animals is
colonized by numerous microorgan-
protease from (AD), and folliculitis (Saunders et al.,
isms that constitute the skin micro- Malassezia globosa 2012). It is presumed that Malassezia
strains associated with these clinical
biome. These include commensal exhibits unexpected conditions are derived from normal
bacteria and fungi that establish a hydrolytic activity
nonpathogenic interaction with the commensal strains, but this has
host, but in certain circumstances, such that acts on not been experimentally proven. As
as immune conditions within the host, Staphylococcus a result, the pathophysiology of
or intrinsic microbial imbalance, some Malassezia and the mechanisms that
aureus biofilms. govern its shift from commensal to
commensals can become pathogenic or
beneficial. The study by Li et al. (2018) pathogen are poorly understood.
reports a previously unknown benefi- Malassezia species are the most It is reasonable to hypothesize that
cial role for a secreted aspartyl protease abundant fungal skin inhabitant of the immune system has adapted to the
produced by the fungus Malassezia humans (Findley et al., 2013). This commensal nature of Malassezia and
globosa. genus includes a monophyletic group thus tolerates its presence on the skin,
but the immune system can also
recognize the fungus as a pathogen and
1
Department of Molecular Genetics and Microbiology, Duke University Medical Center, Durham, respond. Malassezia can be recognized
North Carolina, USA; and 2Science for Life Laboratory, Department of Clinical Science and Education,
Karolinska Institutet, and Sachs’ Children and Youth Hospital, Södersjukhuset, Stockholm, Sweden
by the host, either directly through
Correspondence: Annika Scheynius, Department of Clinical Science and Education, Karolinska Institutet,
membrane-bound pattern recognition
and Sachs’ Children and Youth Hospital, Södersjukhuset, SE-118 83 Stockholm, Sweden. E-mail: annika. receptors or indirectly through produc-
scheynius@ki.se tion of inflammatory metabolites
ª 2018 The Authors. Published by Elsevier, Inc. on behalf of the Society for Investigative Dermatology. released by hydrolysis of sebum by

1026 Journal of Investigative Dermatology (2018), Volume 138


COMMENTARY

Figure 1. Staphylococcus aureus biofilms are inhibited by an aspartyl protease secreted by Malassezia globosa. On the left, a schematic view illustrates
a biofilm formed on the skin by the bacterium S. aureus and the inflammation that is produced as a host response. On the right, formation of the biofilm is
inhibited by the secreted aspartyl protease MgSAP1 of M. globosa, and as a consequence, there is predicted to be reduced inflammation of the skin.

fungal lipases and proteases. These interfering with the host RNAi ma- secreted aspartyl protease 1). Further
metabolites are thought to be respon- chinery to silence host immune genes analyses demonstrated that MgSAP1
sible for clinical dandruff and sebor- and cause infection (Weiberg et al., has a cleavage preference adjacent
rheic dermatitis (White et al., 2014). 2013). to aromatic residues, in particular
Another way in which Malassezia is Although establishing the basis and tryptophan, which distinguishes it from
known to interact with the immune the relationship between commen- other known proteases.
system is through the production of salism and pathogenicity is a recog- Li et al. then aimed to establish if the
specific allergens. These include a nized and active research field, secreted protease MgSAP1 was (1)
set of nine conserved and four Malassezia interactions with other produced in situ on human skin, (2) had
unknown proteins identified in the microbes on the skin and their effects any role in Malassezia biology and/or
M. sympodialis genome (Gioti et al., on the host are largely unexplored. Li pathophysiology, and (3) could poten-
2013). Approximately half of adult pa- et al. (2018) reported that a secreted tially mediate interactions with existing
tients with AD have allergen-specific aspartyl protease produced by skin microflora. MgSAP1 was found to
IgE and T-cell reactivity to Malassezia, M. globosa displays antibiofilm prop- be expressed on the faces of 17 of 18
which are rarely observed in respiratory erties against Staphylococcus aureus, healthy male and female volunteers,
allergies, suggesting a host-microbe which is responsible for skin and soft indicating its ubiquitous production.
interaction related to the skin environ- tissue infections and which is Among the skin microflora, S. aureus
ment in AD (White et al., 2014). A frequently associated with skin in- coexists in many sites with M. globosa
clinical hallmark of AD is dry, itchy skin fections in AD. Previous genomic (Oh et al., 2014) and produces protein
with increased permeability and water studies revealed a robust secretory A (SpA), which is essential for biofilm
loss. There is a distinct reciprocal repertoire for all species belonging to formation, a major S. aureus virulence
expression pattern of induced inflam- the genus Malassezia, consistent with factor (Archer et al., 2011). Because
matory genes and repressed lipid the importance of these hydrolytic en- SpA is rich in lysine and aromatic resi-
metabolism genes (Sääf et al., 2008). zymes for Malassezia biology and dues, the authors hypothesized that it
This results in an inhospitable environ- pathophysiology (Wu et al., 2015; Zhu could be hydrolyzed by MgSAP1, thus
ment for the lipid-dependent Malasse- et al., 2017). impacting S. aureus pathogenicity.
zia, and there is an increased pH level RNAseq analysis revealed that 2 of Strikingly, MgSPA1 rapidly degraded
on AD skin that stimulates the yeast to the 15 predicted aspartyl proteases of recombinant SpA in vitro and strongly
release more allergens compared with M. globosa, encoded by MGL_3328 reduced the in situ volume of S. aureus
culture at normal skin pH (Selander and MGL_1932, were highly expressed biofilm formation without affecting
et al., 2006). in vitro during growth in both rich and bacterial viability. A representation of
Yet another way for Malassezia to minimal media. Through biochemical MgSAP1-mediated biofilm destruction
communicate with the host is through analyses, Li et al. (2018) characterized is shown in Figure 1.
the release of extracellular nanosized a specific aspartyl protease activity, This study raises questions about the
vesicles, designated MalaEx, that carry revealing strong cleavage of specific specific roles of Malassezia proteases, as
allergens and can induce inflammatory substrates (RPKPYAvWM and their common in situ expression has
cytokine responses (Gehrmann et al., RPKPVEvWR), increasing activity in the been correlated with their involvement
2011). MalaEx, which contain small first 16 hours of growth, and a pH in pathogenesis (White et al., 2014). This
RNAs as a cargo (Rayner et al., 2017), optimum between 4 and 5. Mass predicted function as virulence factors is
have the potential—like other fungal spectrometry and trypsin in-gel digest likely based on the role of analogous
extracellular vesicles—to deliver func- analyses identified MGL_1932 as the proteases in more well-studied fungi that
tional mRNAs and microRNA-like major aspartyl protease in culture, and it can live on the skin such as the derma-
RNAs to recipient host cells, thereby was named MgSAP1 (from M. globosa tophytes and C. albicans. In fact, their

www.jidonline.org 1027
COMMENTARY
genome comparisons reveal a signifi- determine the function of unknown de Hoog S, Monod M, Dawson T, Boekhout T,
Mayser P, Gräser Y. Skin fungi from coloniza-
cant expansion of genes predicted to proteins during microbial interactions,
tion to infection. Microbiol Spectr 2017;5.
encode proteases in Malassezia, der- and the beneficial or detrimental FUNK-0049-2016.
matophytes, and C. albicans, suggesting impact that they might have on the Findley K, Oh J, Yang J, Conlan S, Deming C,
an important role of proteases in evolu- host. For example, whether the char- Meyer JA, et al. Topographic diversity of fungal
tion and adaptation on the skin. In acterized MgSAP1 protease also plays a and bacterial communities in human skin.
Nature 2013;498:367e70.
C. albicans, secreted aspartyl proteases role in Malassezia pathogenesis as
Gehrmann U, Qazi KR, Johansson C, Hultenby K,
have long been recognized as virulence described for other aspartyl proteases is
Karlsson M, Lundeberg L, et al. Nanovesicles
factors that act by promoting adhesion still unknown. There is a crucial need to from Malassezia sympodialis and host exo-
to, invasion of, and damage to epithelial develop and establish reliable somes induce cytokine responses—novel
cells and tissues and by inducing the host-pathogen models to study how mechanisms for host-microbe interactions in
atopic eczema. PLoS One 2011;6:e21480.
secretion of proinflammatory cytokines Malassezia interacts with both cells in
Gioti A, Nystedt B, Li W, Xu J, Andersson A,
independently from their proteolytic the skin and different immune cells, Averette AF, et al. Genomic insights into the atopic
activity (Pietrella et al., 2010). With and with other microbes that live on the eczema-associated skin commensal yeast Malas-
respect to dermatophytes, these fungi skin, as well as the induced immune sezia sympodialis. mBio 2013;4. e00572e12.
secrete an abundance of proteases for responses in robust mouse and Graham CE, Cruz MR, Garsin DA, Lorenz MC.
multiple functions, such as adherence humanized-mouse models of infection. Enterococcus faecalis bacteriocin EntV inhibits
hyphal morphogenesis, biofilm formation, and
on the skin, keratin digestion for pene- This coupled with the recent develop- virulence of Candida albicans. Proc Natl Acad
tration, and modulation of cell meta- ment of tools for targeted and inser- Sci USA 2017;114:4507e12.
bolism and the host immune system (de tional mutagenesis (Celis et al., 2017; Ianiri G, Averette AF, Kingsbury JM,
Hoog et al., 2017; White et al., 2014). Ianiri et al., 2016) will help to charac- Heitman J, Idnurm A. Gene function anal-
The study by Li et al. (2018) repre- terize the mechanisms that establish the ysis in the ubiquitous human commensal
and pathogen Malassezia genus. mBio
sents a paradigmatic example of a commensal, pathogenic, and beneficial 2016;7:e01853e16.
fungal-bacterial interaction that is lifestyles of Malassezia species on the
Li H, Goh BN, Teh WK, Jiang Z, Goh JPZ, Goh A,
mediated by a secreted molecule and skin. et al. Skin commensal Malassezia globosa
that potentially results in a beneficial secreted protease attenuates Staphylococcus
effect for the host. Fungal and bacterial CONFLICT OF INTEREST aureus biofilm formation. J Invest Dermatol
AS has co-authored large collaborative publica- 2018;138:1137e45.
interactions are common, although
tions with the senior author (Tom Dawson) of the Oh J, Byrd AL, Deming C, Conlan S, Kong HH,
they are understudied and technically present article commented on herein, published Segre JA. Biogeography and individuality shape
challenging to elucidate. However, in 2013 (Gioti et al., 2013), 2014 (White et al., function in the human skin metagenome.
there is an increasing awareness of their 2014), 2015 (Wu et al., 2015), and 2017 (Zhu Nature 2014;514:59e64.
et al., 2017). This did not influence the views
biological and pathophysiological presented here with respect to the Commentary Peleg AY, Hogan DA, Mylonakis E. Medically
importance (Peleg et al., 2010). As an published in the Journal of Investigative Derma- important bacterial-fungal interactions. Nat Rev
example, Graham et al. (2017) recently tology. JH has co-authored large collaborative Microbiol 2010;8:340e9.
described an interesting interaction publications with the senior author (Tom Dawson) Pietrella D, Rachini A, Pandey N, Schild L,
of the article discussed, published in 2013 (Gioti Netea M, Bistoni F, et al. The inflammatory
between the bacterium Enterococcus et al., 2013), 2015 (Wu et al., 2015), and 2017 response induced by aspartic proteases of
faecalis and C. albicans. These two (Zhu et al., 2017). This did not influence the views Candida albicans is independent of proteolytic
microbes occupy overlapping niches in presented here with respect to the article pub- activity. Infect Immun 2010;78:4754e62.
lished in the Journal of Investigative Dermatology.
the mammalian microbiome and Rayner S, Bruhn S, Vallhov H, Andersson A,
AS has research support from the Swedish Research
display antagonistic activity resulting in Billmyre RB, Scheynius A. Identification of
Council Medicine, the Cancer and Allergy Foun-
small RNAs in extracellular vesicles from the
reduced virulence for both microbes. In dation, the ChAMP (Centre for Allergy Research
commensal yeast Malassezia sympodialis. Sci
C. albicans, this reduced virulence was Highlights Asthma Markers of Phenotype) con-
Rep 2017;7:39742.
sortium that is funded by the Swedish Foundation
attributed to the reduction of hyphal for Strategic Research, the Karolinska Institutet, Sääf AM, Tengvall-Linder M, Chang HY, Adler AS,
development and biofilm formation AstraZeneca and Science for Life Laboratory Joint Wahlgren C-F, Scheynius A, et al. Global
due to the activity of the secreted Research Collaboration. AS is a member in the Joint expression profiling in atopic eczema reveals
Steering Committee for the Human Translational reciprocal expression of inflammatory and lipid
E. faecalis bacteriocin, EntV (Graham genes. PLoS One 2008;3:e4017.
Microbiome Program at SciLifeLab/Karolinska
et al., 2017). Institutet together with Ferring Pharmaceuticals, Saunders CW, Scheynius A, Heitman J. Malassezia
Switzerland, during 2016e2018, outside the scope fungi are specialized to live on skin and asso-
Conclusions of this work and without any financial support. GI ciated with dandruff, eczema, and other skin
states no conflict of interest. diseases. PLoS Pathog 2012;8:e1002701.
The study of Li et al. (2018) reveals that
the commensal and sometimes patho- Selander C, Zargari A, Mollby R, Rasool O,
REFERENCES Scheynius A. Higher pH level, corresponding to
genic fungus M. globosa produces an that on the skin of patients with atopic eczema,
aspartyl protease, unique in its evolu- Archer NK, Mazaitis MJ, Costerton JW, Leid JG,
Powers ME, Shirtliff ME. Staphylococcus aureus stimulates the release of Malassezia sympodia-
tionary trajectory and substrate speci- biofilms: properties, regulation and roles in lis allergens. Allergy 2006;61:1002e8.
ficity, which impacts a recognized human disease. Virulence 2011;2:445e59. Sparber F, LeibundGut-Landmann S. Host
virulence attribute of a commensal and Celis AM, Vos AM, Triana S, Medina CA, responses to Malassezia spp. in the mammalian
skin. Front Immunol 2017;8:1614.
pathogenic bacteria, thus potentially Escobar N, Restrepo S, et al. Highly efficient
transformation system for Malassezia furfur Weiberg A, Wang M, Lin FM, Zhao H, Zhang Z,
resulting in unexpected benefits for the Kaloshian I, et al. Fungal small RNAs suppress
and Malassezia pachydermatis using Agro-
host. This finding underscores the bacterium tumefaciens-mediated trans- plant immunity by hijacking host RNA interfer-
importance of in vivo studies to formation. J Microbiol Methods 2017;134:1e6. ence pathways. Science 2013;342:118e23.

1028 Journal of Investigative Dermatology (2018), Volume 138


COMMENTARY
White TC, Findley K, Dawson TL Jr, Scheynius A, on human skin. PLoS Genet 2015;11: within the lamina lucida); dystrophic EB
Boekhout T, Cuomo CA, et al. Fungi on the skin: e1005614.
demonstrating sublamina densa blis-
dermatophytes and Malassezia. Cold Spring Zhu Y, Engstrom PG, Tellgren-Roth C, Baudo CD,
Harb Perspect Med 2014;4:a019802. tering within the upper papillary dermis;
Kennell JC, Sun S, et al. Proteogenomics pro-
Wu G, Zhao H, Li C, Rajapakse MP, Wong WC, duces comprehensive and highly accurate and Kindler syndrome with multiple
Xu J, et al. Genus-wide comparative protein-coding gene annotation in a complete levels of blistering. The treatment of
genomics of Malassezia delineates its phy- genome assembly of Malassezia sympodialis. these different forms of EB relies pri-
logeny, physiology, and niche adaptation Nucleic Acids Res 2017;45:2629e43.
marily on prevention of trauma and in-
fections, and there is no specific cure for
See related articles on pgs 1157 and 1228 this, currently intractable group of dis-
orders. However, over the past decade,
and especially over the past few years,
The Conundrum of Allogeneic there has been considerable progress in
understanding the mechanistic details
Bone Marrow Transplantation leading from the genetic defects into
blistering phenotypes, and preclinical
for Epidermolysis Bullosa work has suggested a number of poten-
tial treatment approaches, some of
Jouni Uitto1 which have been extended to the level
of early clinical trials.
Epidermolysis bullosa is a heterogeneous group of heritable blistering disorders One of the first early clinical trials
with considerable morbidity and mortality. Currently, there is no effective for the systemic treatment of EB
treatment or cure for epidermolysis bullosa, but bone marrow transplantation consisted of allogeneic whole bone
has been suggested to improve the clinical presentation and quality of life of marrow transplantation (BMT), reported
some patients with the recessive dystrophic subtype of epidermolysis bullosa. In in 2010, in patients with severe recessive
this issue, two studies (Hünefeld et al., and Egawa and Kabashima) address the dystrophic EB (RDEB) (Wagner et al.,
issue whether bone marrow transplantation could be applied to patients with 2010). More than 40 children with
epidermolysis bullosa simplex with intraepidermal blistering. Utilizing a either RDEB or junctional EB have now
desmoglein-3 mouse model (Dsg3/) or keratin 5-specific reporter mice, the undergone BMT worldwide. Although
investigators show that transplanted bone marrow-derived cells migrate to the the results of the clinical experience
skin of bone marrow transplantation recipient mice, but these cells fail to involving the full cohort of these patients
transdifferentiate into epidermal keratinocytes, and there was no improvement have yet to be published, it appears that
in the clinical manifestations of the Dsg3/ mice. Thus, further preclinical beneficial clinical response, but not
experimentation, possibly using mouse models that more faithfully recapitulate cure, can be noted in some, but not all,
the epidermolysis bullosa simplex phenotype, is advisable before commencing children with RDEB after BMT. Although
clinical trials of bone marrow transplantation for epidermolysis bullosa simplex. experience with BMT in junctional EB is
Journal of Investigative Dermatology (2018) 138, 1029e1031. doi:10.1016/j.jid.2017.12.009 limited, this approach does not appear
to have any therapeutic value for this
type of EB (Hammersen et al., 2016;
Epidermolysis bullosa (EB), a group influenced by the topographic expres- Hook et al., 2017). In this issue of the
of heritable blistering disorders, pre- sion of the affected genes within the Journal, two complementary studies
sents with a spectrum of phenotypic cutaneous basement membrane zone, now ask if BMT might be applicable to
severity, with the primary manifesta- the types and combinations of the EBS characterized by intraepidermal
tions relating to skin and mucous mutations, and their consequences at blistering (Egawa and Kabashima, 2018;
membrane fragility (Fine et al., 2014). the mRNA and protein levels (Uitto Hünefeld et al., 2018). As a disease
In the most severe forms, patients et al., 2016; Vahidnezhad et al., 2018). model, Hünefeld and coworkers
affected with this disease die within a Based on ultrastructural demonstration employ a desmoglein-3 knockout mouse
few weeks or months of life, whereas in of the level of blistering within the (Dsg3/) that demonstrates blistering
the milder forms, affected individuals skin and clinical presentations, EB has exclusively within the epidermis and
exhibit life-long blistering that does been divided into four broad categories: mucosal membranes, clinically mani-
not affect longevity. This spectrum of EB simplex (EBS) with intraepidermal festing with perioral erosions and a run-
phenotypic severity reflects the fact blistering; junctional EB with tissue ted phenotype, and no significant
that mutations in as many as 20 distinct separation within the dermal-epidermal increase in mortality in the first 4e6
genes can underlie the EB phenotype, basement membrane itself (primarily months of life. BMT was performed at
8e10 weeks after the birth using bone
1
marrow cells from enhanced green
Department of Dermatology and Cutaneous Biology, Sidney Kimmel Medical College, Thomas
Jefferson University, Philadelphia, Pennsylvania, USA
fluorescent protein (EGFP) expressing
Correspondence: Jouni Uitto, Department of Dermatology and Cutaneous Biology, Sidney Kimmel
wild-type Dsg3þ/þ mice that can be used
Medical College at Thomas Jefferson University, 233 S. 10th Street, Suite 450 BLSB, Philadelphia, to track the engraftment and migration of
Pennsylvania 19107, USA. E-mail: Jouni.Uitto@Jefferson.edu the transplanted cells. Ten weeks after
ª 2017 The Author. Published by Elsevier, Inc. on behalf of the Society for Investigative Dermatology. BMT, the distribution of donor cells was

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