This document discusses Malassezia associated skin diseases. It notes that fungal infections affect around 1 billion people globally. Malassezia yeasts can cause both inflammatory and non-inflammatory skin conditions like pityriasis versicolor, folliculitis, seborrheic dermatitis, and atopic dermatitis. The document explores sampling methods for Malassezia on skin, genetic variations between strains, and interactions with the skin environment and host. It is suggested that certain Malassezia metabolites produced from tryptophan, like indolo-3-carboxaldehyde and indolo[3,2-b]carbazole, may contribute to diseases by regulating melanin synthesis, inducing

1. Update on the Malassezia associated skin diseases.
A. Velegraki
Dept. of Microbiology
Medical School
National and Kapodistrian University of Athens
25/11/2016

2. Disclaimer
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Unrestricted research grants & honoraria
Astellas
Gilead
L’Oréal, Paris (R&D)
MSD
Pfizer
Procter & Gamble, USA (R&D)

3. One health Concept
• Unites Human Health,
Animal Health, and the
Environment
• Promotes communication and collaboration
among people working in different fields
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4. On that premise
• Fungal infections of skin, hair and nails affect
~1 billion people globally.
• In the US studies estimated 4M outpatient
medical visits.
Vos et al. Lancet 2012; 380:2163–2196
Panackal et al. Int J Dermatol. 2009 Jul;48(7):704-12.
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5. Non-inflammatory condition
pityriasis versicolor (PV)
PLoS Pathog 11(1): e1004523. doi:10.1371/journal.ppat.1004523
http://journals.plos.org/plospathogens/article?id=info:doi/10.1371/journal.ppat.1004523
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6. Inflammatory conditions I
Folliculitis Seborrhoeic dermatitis
PLoS Pathog 11(1): e1004523. doi:10.1371/journal.ppat.1004523
http://journals.plos.org/plospathogens/article?id=info:doi/10.1371/journal.ppat.1004523
Courtesy E. Guého, in Malassezia and the Skin, Springer 2010
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7. Seborrheic Dermatitis and Dandruff
Schwartz et al. Acta Derm Venereol. 2013 27;93:131-7

8. Seborrhoeic blepharitis Demodex blepharitis
Inflammatory conditions II
(Malssezia and its . . skin microbiome “ally?”)
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9. Atopic dermatitis
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Malassezia yeasts seem to participate
in the extrinsic and intrinsic forms of AD
Bieber T. N Engl J Med 2008;358:1483-94;
Sugita T. et al. J Clin Microbiol 2001; 39: 3486–3490
Saunders et al. PLoS Pathog. 2012;8(6):e1002701. doi: 10.1371/journal.ppat.1002701.
Gaitanis et al. Clinics in Dermatol. 2013; 31, 445-463

10. Gathering evidence on the presence of
Malassezia in lesions and healthy skin
Culture on non- culture?
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11. Skin specimen test procedures
Updating the old question
• Swabs
• Scrapings
• Washing
• Scotch tape
• Transparent dressing,
Opsite™ (Smith &
Nephew)
• Microscopy (KOH,
fluorescence, gram
stain)
• Culture media modified
Dixon (mDIX),
Leeming and
Notman agar (LNA)
• Real time PCR
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12. Sampling with Opsite™ and testing by
real time PCR
Sugita et al. In Malassezia and the Skin, Springer Verlag, Berlin-Heidelberg 2010
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13. But need strain
Kolecka et al. Brit J Dermatol. 2014; 170: 332-341
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14. Malassezia pachydermatis
• Thus far the most polymorphic
lipophilic yeast (phenonotypically
and genotypically.
• In constant interaction with
animal skin microenvironment
• Isolated from the skin of diverse
range of carnivore animals and
the skin of humans (dog owners)
• Become pathogenic under the influence of predisposing factors
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Midreuil et al. Int J Syst Bacteriol 1999; 49: 1287–1294
Cafarchia et al. J Clin Microbiol 2004; 42: 4868–4869
Bond et al. In: Malassezia and the Skin 2010. Springer.
pp 271–299.

15. Human skin
Malassezia yeasts
Genetic
variations
Environmentalf
actors
Genetic
variations
Environmentalf
actors
Susceptible individuals - genetic
predisposition
Pathogenic strains
Pathogenicity traits
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16. In extreme environments
Sugita et al. Med. Mycol. 2015, 53, 717-724; Med. Mycol 2016,
doi 10.1093/mmy/myv121
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17. Interactions with the epidermis and properties
of the Malassezia metabolome:
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Gaitanis et al. Clinics in Dermatol. (2013) 31,455-436
Enzymes & allergens sensitize susceptible hosts.
Indole metabolites modify the function of melanocytes & dendritic cells

18. The Malassezia metabolome and its
properties
Melanin production
Tryptophan as sole nitrogen
source indole alkaloid
production
Mayser P et al, Arch Dermatol Res. 1998;290(5):277-82.
Gaitanis et al. J Clin Microbiol. 2005; 43: 4147-51
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19. Extracts from L-tryptophan grown M. furfur
strains isolated by HPLC & characterized by NMR
and Mass spectroscopy
Healthy skin isolates Seborrheic dermatitis
isolates
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20. Gaitanis et al. J Invest Dermatol. 2008 Jul;128(7):1620-5.
Mexia et al. Arch Biochem Biophys. 2015 Apr 1;571:16-20
Giatanis et al. Med Hypotheses. 2011 Jul;77(1):47-51
Indicative Extracts
• M. furfur extracts from
SD and healthy skin
• A: indolo-3-
carboxaldehyde
• M: Malassezin
• ICZ: indolo[3,2-b]
carbazole (Novel
isolate)
• P: pityriacitrin
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21. Malassezin
Indicative bioactive properties
• Reduces melanin synthesis
and inhibits transfer of
melanin from melanocytes
to keratocytes
• Induces the apoptosis of
melanocytes
• It is an AhR ligand although
it does not fulfill the basic
structural characteristics.
No sunburn?
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22. Model showing the putative interactions of Malassezia yeasts
with the skin.
Velegraki A, Cafarchia C, Gaitanis G, Iatta R, Boekhout T (2015) Malassezia Infections in Humans and Animals: Pathophysiology, Detection, and
Treatment. PLoS Pathog 11(1): e1004523. doi:10.1371/journal.ppat.1004523
http://journals.plos.org/plospathogens/article?id=info:doi/10.1371/journal.ppat.1004523
25/11/2016

23. indolo[3,2-b] carbazole (ICZ)
Bioactivity
• One of the most active AhR
agonists (dioxin receptor) in
vitro (EC50=2.6x10-7M)
• Regulates AhR expression
depended genes like dioxin
but it is removed from the
body and does not exhibit
the dioxin toxic
• Induces transientCYP1A1 in
the liver
Are Malassezia metabolites
active against other fungi
of the skin microbiota or
oter pathogenic fungi?
What is the concentration
of these metabolites in the
skin?
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24. Malassezia indole inhibitory activity
• Against Aspergillus, Candida Cryptococcus,
Rhizopus, Fusarium spp. and Exophiala
dermatitidis
• These concentrations are significant as they
are detectible in loco (diseased skin)
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Velegraki et al. Spring EADV, 2016

25. Conclusions
• Malassezia infections are of public health significance
• Human and other vertabrate Malassezia commencals interact with
the environment leading to increased colonization and disease.
• Malassezia L-tryptophan alkaloids are statistically correlated with
disease severity: seborrhoic dermatitis > pityriasis versicolor >
dandruff > healthy
• Malassezia inflammatory conditions may be risk factors for other skin
diseases due to their metabolite interactions with the host and
response to the UV intensity and dosimetry
• Malassezia metabolites show activity against other fungi.
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26. 26
Malassezia and the skin. Springer-Verlag, 2010
Τα ινδολικά παράγωγά τους
διεγείρουν τον
υποδοχέα διοξίνης (AhR)
in loco (δέρμα)
Journal of Investigative Dermatology advance online publication, 4 April 2013