See discussions, stats, and author profiles for this publication at: https://www.researchgate.

net/publication/42610384

Pathogenesis of dermatophytosis and tinea versicolor

Article  in  Clinics in dermatology · March 2010

DOI: 10.1016/j.clindermatol.2009.12.015 · Source: PubMed

CITATIONS READS

52 1,328

1 author:

Luis Javier Méndez-Tovar

Universidad Nacional Autónoma de México
63 PUBLICATIONS   762 CITATIONS   

SEE PROFILE

Some of the authors of this publication are also working on these related projects:

Hepatotoxicity View project

Human innate immune response to fungi. View project

All content following this page was uploaded by Luis Javier Méndez-Tovar on 17 August 2017.

The user has requested enhancement of the downloaded file.

Clinics in Dermatology (2010) 28, 185–189

Discussion

Pathogenesis of dermatophytosis and tinea versicolor

Luis J. Mendez-Tovar, MD
Laboratory of Dermatology and Medical Mycology Research, Specialties Hospital, National Medical Center, IMSS,
Apdo postal A-032, Coahuila No 5 Col Roma, 06703, México, DF, México

Abstract Dermatophytoses are infections caused by keratinophilic fungi known as dermatophytes.

Several steps are required for infection to take place: contact, adherence, and invasion of keratin layers.
The severity of the infection depends on the type of agent, environmental factors, and the host
immunologic status. Tinea versicolor is caused by the Malassezia spp yeasts, which are microorganisms
that belong to normal biota in seborrheic areas, but some contributing factors, such as the application of
oily preparations, creams, an increase in ambient humidity, corticosteroid abuse, or genetic
predisposition can induce its overgrowth in both filamentous and yeast structures. Exposure to sunlight
stimulates the production of azelaic acid, which causes the appearance of hypopigmented spots.
Currently, there is no scientific explanation for hyperpigmented lesions.
© 2010 Published by Elsevier Inc.

Dermatophytosis contact can be with family members, in work situations (people

Dermatophytes are keratinophilic fungi that probably
appeared in the Mesozoic Age.1 In the beginning, they
lived in the soil (geophilic). Later, through frequent contact
with animals and humans, some species adapted to the hosts,
causing infections. The fungi that affect animals are called
zoophilic dermatophytes, whereas those that mainly affect
humans are known as anthropophilic dermatophytes. 2
Dermatophytoses are the most common mycoses worldwide.
Thus, understanding the physiopathogenesis of these infec-
tions is essential for preventing and treating them efficiently.3
Infection mechanism
Human infection occurs through contact with contaminated
products or specimens, such as soil, hair, or animal epidermal
scales (pets, work animals, or fur farming), as well as with
those who have frequent contact with affected individuals. This
E-mail address: ljmt@servidor.unam.mx.
who live in dormitories or barracks), or by sharing personal
belongings such as combs, shoes, or clothing.4,5
Owing to anatomic or environmental factors, some areas
of the body are more susceptible to the development of
dermatophyte infections. The fungi under the distal nail area
remains in contact with the skin and nails for several hours or
even days. This allows for the growth and eventual invasion
of the keratin layers of the nail. The spaces between the
fingers, where factors such as sweat, maceration, and
alkaline pH are present, provide the proper environment
for the development of these fungal diseases. Fungal conidia
that fall on the scalp are protected by the hair. They remain in
contact with the skin for a long time and can cause tinea
capitis. Local conditions in the groin also favor infection,
because the point where the scrotum joins the thigh forms an
intertriginous area with suitable humidity, temperature, and
nutrients for the growth of dermatophytes.
The amount of inocula for a spontaneous infection has not
been established. Some in vivo studies in the last century
showed that the infecting dose on hairless skin is six conidia.
In affected people with normal immunity, a hypersensitivity

0738-081X/$ – see front matter © 2010 Published by Elsevier Inc.

doi:10.1016/j.clindermatol.2009.12.015
186
response develops in 30 days, and spontaneous recovery
generally occurs within 50 days.6
Adherence
In in vitro models, Trichophyton mentagrophytes requires
approximately 6 hours to adhere firmly, even though
germination begins after 4 hours. In other models using
layers of fingernail keratin, adherence occurs after 6 hours
and germination of the conidia and branching after 16 hours.
Other experiments using skin cross-sections showed that 12
hours was necessary for adherence, 16 hours for germination,
and 72 hours for invasion of the stratum corneum.7
Although no linking mechanism has been demonstrated
between dermatophytes and the stratum corneum, it has been
suggested that dermatophytes possess specific adhesins for
some carbohydrates present on the skin surface. These are
probably similar to the aspartic proteases involved in the
adherence of Candida.8,9
Growth on keratinized tissues
Once dermatophytes have adhered to keratinized tissue,
they release enzymes (keratinases, metalloproteases, and
serine proteases) and also produce lipases and ceramides.
The production of these enzymes is induced by the
substrate on which they develop, but this has not yet
been studied at a molecular level. One of the gene families
that is probably involved is the GATA family. In Micros-
porum canis, the disruption of the dnr-1 gene blocks the
development of the fungus if the culture medium includes
only a keratin substrate.10
Studies of T rubrum suggest that the production of some
endoproteases is overruled by other factors associated with
zinc, which is activated in the presence of an acid pH.11
The released enzymes, aside from breaking the bonds of
the keratinized tissue, behave as antigens and induce various
degrees of inflammation. As a result, tissue damage is a
combination of the enzymatic action of the dermatophytes
and the defense mechanisms activated during the inflamma-
tory processes.12
Immune response
The infections caused by dermatophytes generally induce
a mainly Th1-type adaptive immune response with the
production of proinflammatory cytokines like interleukin
(IL)-2 and interferon (IFN)-γ. The immunologic response
varies among the different species of dermatophytes. It is
more intense when the infection is caused by zoophilic or
geophilic dermatophytes and is weak when the infection is
caused by anthropophilic dermatophytes.13
Two factors account for the difference in the degree of
immunologic response. The first factor is the type of
metabolites and enzymes released by the agent: the more
L.J. Mendez-Tovar
foreign they are, the greater the molecular weight and
complexity of the antigen they have, the immune response is
more vigorous. For example, the response generated against
subtilisin (Sub3), a metalloprotease found in M canis,
generates an intense inflammation.14
The second factor is the immunosuppression, caused by
the metabolites in anthropophilic dermatophytes, as occurs
with T rubrum mannans.15 In vitro, these compounds
inhibit the cellular proliferation of lymphocytes and also
cause a delay in the replacement of the stratum corneum of
the skin.16 Although these mannans are present in most
fungi, this immunosuppressive effect is present in only
some fungi species; the precise mechanism for their action
is not yet understood.17
Other studies performed on keratinocytes with metabolic
products from T rubrum show that they release a small
amount of IL-1α; in contrast, these same cells produce a
greater amount of IL when metabolites of T mentagro-
phytes are added. These findings correlate with less
symptomatology and infections of longer duration in T
rubrum infection.18
The modulation of the Th1 immune response or of the
polymorphonuclear and macrophage effectors of this
response by dermatophytes is stated in various studies.
Among them are the inhibition of the lymphocytes function
by the T rubrum mannans and the alteration of the
phagocytic capacity of the macrophages. The localization
of the dermatophytes in the stratum corneum is probably
another mechanism for avoiding the development of an
intense cellular immunoresponse.19 In vitro cultures of
mononuclear cells exhibit less proliferation after the
addition of mannans of T rubrum and T tonsurans
(anthropophilic dermatophytes) compared with the prolif-
eration in control groups.
Immunoglobulins (Ig) are also involved in this immune
modulation. In acute infections, there is a cellular-type
immune response occurs in acute infections, whereas high
levels of IgE and IgG4 are detected in chronic infections.
This subclass of Ig increases in chronic pathologies with
poor immunologic responses.20,21
There are still few, although promising, studies for
understanding the genes involved in the pathogenesis of
dermatophyte infections. Genes involved in the production
of enzymes like Sub3 and DppIV are being researched with
particular interest. By using animal models experimentally
infected with genetically modified strains, it will be possible
to better understand the mechanisms involved in the invasion
of keratinocytes.22
Tinea versicolor
Tinea versicolor (TV) is a chronic and benign mycosis,
clinically characterized by the presence of hypochromic or
hyperchromic macules on the face, arms, and trunk. The
Pathogenesis of dermatophytosis and tinea versicolor
dyschromic areas also usually present a fine desquamation.
At first, the macules are 3 to 5 mm in diameter and are
round or oval shaped; with time, the skin lesions may
coalesce, affect extensive areas of the body, and exhibit
irregular forms.23
This superficial mycosis is caused by yeasts of the Ma-
lassezia genus. With the exception of M pachydermatis, all
species of this genus are lipophilic.24 In humans, the
seborrheic areas (scalp, face, and the back and frontal aspect
of the trunk) are always colonized by one or several species
of this genus. The most common are M globosa, M
sympodialis, M sloffiae, and M restricta.25,26 These yeasts
form part of the normal skin biota and their presence
probably blocks the settling of harmful organisms. Environ-
mental modifications or individual immunologic changes
can cause cutaneous or systemic disorders associated with
these yeasts.27
TV is a skin disease directly caused by these yeasts and
the only one in which the lipophilic yeasts of the Malas-
sezia genus exhibit their dimorphic capacity—yeasts as
well as short, septated, and nonbranched filaments. Other
conditions associated with these yeasts are seborrheic
dermatitis,28 folliculitis,29 and even systemic infections.30
In these cases, Malassezia spp only appear in the yeast-
phase form. Various studies have shown that the presence
of yeasts of this genus can modify the evolution of atopic
dermatitis31 and psoriasis.32
Etiology
The genus Malassezia contains 13 species. The yeasts are
round, oval, or cylindrical, show monopolar budding, and are
variably sized between 2.5 and 8 μm depending on the
species. The first seven species, M furfur, M pachydermatis,
M sympodialis, M globosa, M sloffiae, M restricta, and M
obtusa, were established on the basis of morphologic,
biochemical, and physiologic characteristics.33 The use of
molecular techniques in recent years has established the
existence of six other species: M dermatis, M japonica, M
yamatoensis, M equine, M caprae, and M nana. Several of
these latter species are probably varieties of the previously
established species.34
In vitro assays have shown that the ability to form germ or
pseudomycelia tubes is limited to M globosa and M furfur;
both are the most frequent species isolated in clinical cases.
Several authors have consequently suggested that the only
causative agents of TV are M globosa and M furfur and that
other Malassezia spp isolated from scales of TV patients,
such as M sympodialis, M. sloffiae, or M restricta, may be
part of the normal biota and not etiologic agents.27,35
Infection mechanism
The yeasts from the Malassezia genus are part of the
normal biota on the skin; thus, exogenous infections cannot
187
be considered. The first contact with the yeast takes place a
few instants after birth, when the newborn's skin comes
into contact with the skin of an individual who carries the
fungus. From that moment on, these yeasts will be present
for a lifetime.36
Predisposing factors
Given that these yeasts are lipophilic, the presence of fatty
acids on the skin favors the development of these organisms.
In childhood, the sebaceous glands have a low rate of fat
production, and for this reason, there are few of these yeasts.
Because of the action of sex hormones in adolescence, the
release of skin lipids by these glands increases considerably
and Malassezia spp develop in large quantities, only in the
yeast form. From that moment forward, it is possible for TV
to develop in any person wherever the fungus evolves to its
dimorphic form.
Several factors increase the possibility of acquiring TV
lesions. Among the main ones are:
1. the application of oils and oily creams, which provide a
substrate for the development of yeasts;
2. exposure to sunlight, which modifies the metabolism of
the fungus and increases the production of azelaic acid;
3. the administration of corticosteroids, which induces
the growth of yeasts in larger quantities37;
4. genetic predisposition, which is suggested by some
researchers based on clinical observations of twins
who do or do not exhibit the pathology38;
5. malnutrition, which some authors argue, favors the
development of this condition; and
6. hyperhidrosis, which is more frequently associated
with hyperchromic lesions in areas near the natural
folds of the body.39
As occurs in many other opportunistic infections, the
development of TV probably depends on the combination of
various factors in each individual.
Development of macules
Through lipases, Malassezia metabolizes various fatty
acids, such as arachidonic or vaccenic acids, and azelaic
acid is released as one of the metabolites. This acid
inhibits the action of the dopa-tyrosinase enzyme, which
blocks the passage of tyrosine to melanin and consequently
results in the appearance of hypochromic spots. The
histopathologic study of the skin in these areas shows the
presence of melanosomes that are smaller than those found
in normal skin.40-42
An important fact is that the skin in the hypochromic areas
does not show an inflammatory infiltrate. A comparative
study assessing the quantity of granulocytic cells in biopsy
specimens of TV and body ringworm found that there were
188
abundant granulocytic cells in ringworm, but these were
almost absent in TV.43 Another study on M pachydermatis,
M sloofiae, and M sympodialis in the production of
interleukins showed that these species induce IL-1b, IL-6,
IL-8, and tumor necrosis factor-α. This production could be
involved in other pathologies, such as seborrheic dermatitis or
folliculitis, where inflammation is a constant feature.
Nevertheless, M furfur, which is considered the etiologic
agent of TV, does not induce the production of these
cytokines.44 Although TV lesions are not inflammatory, the
presence of large quantities of yeasts and their metabolites
probably induce fine desquamation of the skin, which is
present in all cases. Until now, no studies about metabolites of
this fungus related with desquamation have been published.
We also do not know why Malassezia spp stimulate melanin
production in the dark patches in the hyperchromic variety of
TV. The histologic studies of hyperchromic spots have only
shown melanosomes with a larger-than-usual diameter and
their presence in greater abundance.
Conclusions
The study of the pathogesis of most fungal infections has
been a neglected area for many decades. One of the reasons
is that several fungi can cause the same disease, as can be
seen in the case of dermatophytoses and TV caused by
several species of yeasts of the genus Malassezia. In spite of
this, many important recent advances in the field have
increased our understanding of the pathogenesis of these
superficial mycoses. Detailed knowledge of the mechanisms
behind the adherence of dermatophytes or Malassezia spp,
the molecular patterns associated with these pathogens, the
type of Toll receptors they bind to, and the mechanisms by
which some fungi modulate the local or general adaptive
immune response could be useful for the development of
new methods of prevention and the production of new
therapeutic agents.
References
1. Barbee ML, Taylor JW. From 18s ribosomal sequence data to evolution
of morphology among the fungi. Can J Bot 1995;73(suppl 1):S677-83.
2. Padhye AA, Summerbell RC. The dermatophytes. In: Merz WG, Hay
R, editors. Medical mycology. In: Collier L, Balows A, Sussman M,
editors. Topley & Wilson's microbiology and microbial infections.
Vol. 4. London: Hodder Arnold; 2005. p. 220-43.
3. Weinstock MA, Chren MM. The epidemiology and burden of skin
disease. In: Freedberg IM, Eisen AZ, Wolff K, Austin KF, Goldsmith
LA, Katz SI, editors. Fitzpatrick's dermatology in general medicine.
New York: McGraw-Hill; 2007. p. 4-10.
4. George LK. Epidemiology of the dermatophytoses: sources of
infection, modes of transmission and epidemicity. Ann N Y Acad Sci
1960;89:69-77.
5. Weitzman A, Summerbell RC. The dermatophytes. Clin Microbiol Rev
1995;8:240-59.
L.J. Mendez-Tovar
6. Jone HE. Immune response and host resistance of humans to
dermatophyte infection. J Am Acad Dermatol 1993;28:S12-S18.
7. Aljabre SH, Richardson MD, Scott EM, et al. Adherence of
arthroconidia and germlings of anthropophilic and zoophilic varieties
of Trichophyton mentagrophytes to human corneocytes as an early
event in the pathogenesis of dermatophytosis. Clin Exp Dermatol 1993;
18:231-5.
8. Ollert MW, Sohnchen R, Korting HC, et al. Mechanism of adherence of
Candida albicans to cultures human epidermal keratinocytes. Infect
Immun 1993;61:4560-8.
9. Monod M, Borg-von Zepelin M. Secreted aspartic proteases as
virulence factors of Candida species. Biol Chem 2002;383:1087-93.
10. Scazzocchio C. The fungal GATA factors. Curr Opin Microbiol 2000;3:
126-31.
11. Ferreira-Nozawa MS, Silveira HC, Ono CJ, et al. The pH signaling
transcription factor PacC mediates the growth of Trichophyton rubrum
on human nail in vitro. Med Mycol 2006;44:641-5.
12. Jensen JM, Pfeiffer S, Akaki T, et al. Barrier function, epidermal
differentiation, human beta-defensin 2 expression in tinea corporis.
J Invest Dermatol 2007;127:1720-7.
13. Wagner DK, Sohnle PG. Cutaneous defenses against dermatophytes
and yeasts. Clin Microbiol Rev 1995;8:317-35.
14. Brouta F, Descamps F, Vermout S, Monod M, Losson B, Mignon B.
Humoral and cellular immune response to a Microsporum canis
recombinant keratinolytic metalloprotease (r-MEP3) in experimentally
infected guinea pigs. Med Mycol 2002;41:495-501.
15. Blake JS, Dahal MV, Herron MJ, et al. An immunoinhibitory cell wall
glycoprotein (mannan) from Trichophyton rubrum. J Invest Dermatol
1991;96:657-61.
16. Dahal MV. Suppression immunity and inflammation by products
produced by dermatophytes. J Am Acad Dermatol 1993;28:S19-S23.
17. Campos MR, Russo M, Gomes E, Almeida SR. Stimulation, inhibition
and death of macrophages infected with Trichophyton rubrum.
Microbes Infect 2006;8:372-9.
18. Ogawa H, Summerbell RC, Clemons KV, et al. Dermatophytes and host
defense in cutaneous mycoses. Med Mycol 1998;36(suppl 1):166-73.
19. Gidedey K, Favre B, Quadroni M, Monod M. Closely related
dermatophyte species produce different patterns of secreted proteins.
FEMS Microbiol Lett 2007;267:95-101.
20. Woodfolk JA, Wheatley LM, Piyasena RV, Benjamin DC, Platts-Mills
TA. Trichophyton antigens associated with IgE antibodies and delayed
type hypersensitivity. Sequence homology to two families of
serinproteinases. J Biol Chem 1998;273:29489-96.
21. Méndez-Tovar LJ, Mondragón-González R, Manzano-Gayosso P, et al.
Inmunoglobulinas en pacientes con actinomicetoma por Nocardia
brasiliensis. Rev Argent Microbiol 2004;36:174-8.
22. Vermont S, Tabart J, Baldo A, et al. Pathogenesis of dermatophytosis.
Mycopathologia 2008;166:267-75.
23. Grigoriu D, Delacrétaz J, Borelli D. Pityriasis versicolor. Traité de
Micologie Médicale. Lausanne: Editions Payot; 1988. p. 177-90.
24. Yarrow D, Ahearn DG. Genus 7: Malassezia (Baillon). In: Kreger-van-
Rij NYW, editor. The yeasts, a taxonomic study. Amsterdam: Elsevier;
1984. p. 882-5.
25. Hernández-Hernández F, Méndez-Tovar LJ, Bazan-Mora E, et al.
Especies de Malassezia asociadas a diversas dermatosis y piel sana en
población mexicana. Rev Iberoam Micol 2003;20:141-4.
26. Tarazooie B, Kordbacheh P, Zaini F, et al. Study of the distribution of
Malassezia species in patients with pityriasis versicolor and healthy
individuals in Tehran, Iran. BMC Dermatol 2004;4:5.
27. Crespo-Erchiga V, Gómez-Moyano E, Crespo M. La pitiriasis
versicolor y las levaduras del género Malassezia. Actas Dermatosifilogr
2008;99:764-71.
28. Crespo-Erchiga V, Ojeda MA, Vera CA, et al. Aislamiento e
identificación de Malassezia spp en pitiriasis versicolor, dermatitis
seborreica y piel sana. Rev Iberoam Micol 1999;16:S16-S21.
29. Akaza N, Akamatsu H, Sasaki Y, et al. Malassezia folliculitis is caused
by cutaneous resident Malassezia species. Med Mycol 2008;23:1-7.
Pathogenesis of dermatophytosis and tinea versicolor
30. Barber GR, Brown AE, Kiehn TE, et al. Catheter-related Malassezia
furfur fungemia in immunocompromised patients. Am J Med 1993;95:
365-70.
31. Khrosravi AR, Hedayati MT, Mansouri P, et al. Immediate hypersen-
sitivity to Malassezia furfur in patients with atopic dermatitis. Mycoses
2007;50:297-301.
32. Baker BS, Powles A, Garioch JJ, Hardman C, Fry L. Differential T-cell
reactivity to the round and oval forms of Pityrosporum in the skin of
patients with psoriasis. Br J Dermatol 1997;136:319-25.
33. Guého E, Midgley G, Guillot J. The genus Malassezia with description
of four new species. Antonie van Leeuwenhoek 1996;69:337-55.
34. Cabañes FJ, Hernández JJ, Castellá G. Molecular analysis of Malas-
sezia sympodialis-related strains from domestic animals. J Clin
Microbiol 2005;43:337-55.
35. Crespo-Erchiga V. Delgado VF. Malassezia species in skin diseases.
Curr Op Infect Dis 2002;15:133-42.
36. Marcon MJ, Powell DA. Human infections due to Malassezia spp. Clin
Microbiol Rev 1992;5:101-19.
View publication stats
189
37. Gupta AK, Batra R, Bluhum HBS, et al. Skin diseases associated with
Malassezia species. J Am Acad Dermatol 2004;51:785-98.
38. Hafez M, el-Shamy S. Genetic susceptibility in pityriasis versicolor.
Dermatologica 1985;171:86-8.
39. Burke RC. Tinea versicolor: susceptibility factors and experimental
infection in human beings. J Invest Dermatol 1961;36:389-402.
40. Basset A. Clinique et therapeutique des affections à levures lipophiles.
Bull Soc Fr Mycol Med 1998;17:277-82.
41. Nazzaro-Porro M, Passi S. Growth requirements and lipid metabolism
of Pityrosporum orbiculare. J Invest Dermatol 1976;66:176-82.
42. Breathnach AS, Nazzaro-Porro M, Passi S. Azelaic acid. Br J Dermatol
1984;111:115-20.
43. Wroblewski N, Bär S, Mayser P. Missing granulocytic infiltrate in
pityriasis versicolor—indication of specific anti-inflammatory activity
of the pathogen? Mycoses 2005;48(suppl 1):66-71.
44. Watanabe S, Kano R, Sato H, et al. The effects of Malassezia yeasts on
cytokine production by human keratinocytes. J Invest Dermatol 2001;
116:769-73.