Mycopathologia (2008) 166:267275

DOI 10.1007/s11046-008-9104-5

Pathogenesis of Dermatophytosis
Sandy Vermout Jeremy Tabart Aline Baldo
Anne Mathy Bertrand Losson Bernard Mignon

Received: 15 October 2007 / Accepted: 30 January 2008 / Published online: 14 May 2008
Springer Science+Business Media B.V. 2008

Abstract Despite the superficial localization of

most dermatophytosis, host-fungus relationship in
these infections is complex and still poorly elucidated. Though many efforts have been accomplished
to characterize secreted dermatophytic proteases at
the molecular level, only punctual insights have been
afforded into other aspects of the pathogenesis of
dermatophytosis, such as fungal adhesion, regulation
of gene expression during the infection process, and
immunomodulation by fungal factors. However, new
genetic tools were recently developed, allowing a
more rapid and high-throughput functional investigation of dermatophyte genes and the identification of
new putative virulence factors. In addition, sophisticated in vitro infection models are now used and will
open the way to a more comprehensive view of the
interactions between these fungi and host epidermal
cells, especially keratinocytes.
Keywords Dermatophytes
Pathogenesis

Trichophyton
Microsporum

S. Vermout
J. Tabart
A. Baldo
A. Mathy

B. Losson
B. Mignon (&)
Department of Infectious & Parasitic Diseases,
Parasitology, Faculty of Veterinary Medicine,
University of Lie`ge, Boulevard de Colonster, 20,
4000 Lie`ge, Belgium
e-mail: bmignon@ulg.ac.be

Abbreviations
DTH
Delayed-type hypersensitivity
IH
Immediate hypersensitivity
Sub
Subtilisin
Mep
Metalloprotease
DppIV Dipeptidyl-peptidase IV
TRM
Trichophyton rubrum mannans
RFE
Reconstructed feline epidermis

Introduction
Understanding the pathophysiological mechanisms
underlying an infection is the rational basis for the
development of therapeutic and prophylactic strategies. In the case of dermatophytosis, the almost
exclusive localization of the causative agents in
keratinized tissues and their ability to secrete keratinolytic activity in vitro have focused research primarily
on fungal secreted proteases. Our knowledge about the
range of potentially keratinolytic proteases produced
by dermatophytes is constantly growing, several of
them being characterized at the molecular level and
having well-known enzymatic properties [16]. However, it is still not clear how dermatophytic fungi
regulate the utilization of numerous proteases to obtain
nutrients from the insoluble cornified substrate they
invade and which additional or alternative roles are
played by these proteins, namely in relation with
adherence or immunomodulation. Likewise, few studies have been carried out to identify potential virulence

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factors other than proteases. Most of these works are

either describing the adhesion and invasion steps of
infection, or dealing with immunosuppressive properties of Trichophyton rubrum.
When compared to most other fungal diseases, hostfungus relationship in dermatophytic infections is
remarkable, in that these fungi affect immunocompetent individuals, but generally invade only superficial
keratinized structures. Anthropophilic and zoophilic
species are obligatory parasites. The clinical expression of dermatophytosis strongly varies depending on
both the host and fungal species. Whereas infection
can be acute and rapidly eliminated through an
efficient innate and specific immune response, some
dermatophyte species, e.g. T. rubrum and Microsporum canis, reach a high degree of adaptation to their
preferred host, and can cause chronic infections with
little or no symptoms. These intriguing aspects of
dermatophytic infections are still to be lightened. This
article intends to gather and summarize available data
about the diverse fields of dermatophytosis pathogenesis; in addition, it provides a general view of the
genetic tools and infection models that were recently
developed and that promise fast and accurate elucidation of dermatophytic infection processes.

Adhering to and Invading Superficial Skin Tissues

The kinetics of adherence to the skin or nail surface
was investigated in several Trichophyton and Microsporum species, using different experimental models
and microscopy techniques. These studies showed a
time-dependent increase in the number of adhering
spores, followed by germination and invasion of the
stratum corneum by hyphae growing in multiple
directions. Zurita and Hay [7] observed that maximum adherence of Trichophyton spp. arthroconidia to
keratinocytes in suspension occurred within 34 h.
Aljabre et al. [8, 9] used stripped sheets of stratum
corneum or separate keratinocytes to demonstrate that
adherence of Trichophyton mentagrophytes arthroconidia is maximum by 6 h and that germination of
these spores begins by 4 h. In a nail plate model,
adherence and germination of T. mentagrophytes
arthrospores were observed at 6 h and side branches
at 16 h [10]. The early stages of T. mentagrophytes
infection were investigated using skin explants of full
epidermis thickness [11]. Adherence was maximum

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Mycopathologia (2008) 166:267275

at 12 h, germination had started by 24 h, and

penetration of the stratum corneum occurred after
3 days. In our laboratory, adherence of M. canis
arthrospores was studied in a recently developed
model of reconstructed feline epidermis (RFE) [12];
it was shown to begin by 2 h and to be still increasing
by 6 h (unpublished data).
Little is known about the factors that mediate
adherence of dermatophytes. The ability of T. rubrum
to adhere to epithelial cells has been attributed to
carbohydrate-specific adhesins, expressed on the surface of microconidia [13]. From a morphological point
of view, fibrillar projections have been observed in T.
mentagrophytes during the adherence phase [9, 14]. At
the skin surface, long and sparse fibrils connect fungal
arthroconidia to keratinocytes and to each other, while
in the inner skin layers, newly formed arthroconidia
show thin and short appendices covering their entire
surface; the latter begin to vanish as a large contact area
is established between conidia and skin tissue [14].
Based on the findings made in the yeast Candida
albicans, where secreted aspartic proteases (Saps)
have been shown to play a fundamental role in fungal
adherence to epithelia [1517], we formulated the
hypothesis that dermatophytic-secreted proteases
could facilitate or even be necessary for efficient
adherence. In that context, M. canis-secreted subtilisins, metalloproteases, and dipeptidyl-peptidases are
now being investigated as for their potential involvement in adherence and early invasion steps, using our
RFE model and several specific inhibitors such as
protein prosequences. The unique dipeptidyl-peptidase
IV (DppIV) identified in Trichophyton spp. [6] and M.
canis (manuscript submitted) could also be involved in
the adhesion process, as previously demonstrated in
Porphyromonas gingivalis [18]. Although this phenomenon is independent from enzymatic activity,
membrane-associated DppIV from this pathogenic
bacterium mediates adherence to fibronectin.

Growing on Hard Keratinized Substrates

Dermatophytes are provided with an arsenal of
proteases aimed at the digestion of the keratin network
into assimilable oligopeptides or amino acids. These
fungi secrete multiple serine and metallo- endoproteases (subtilisins and fungalysins, respectively) [25]
formerly called keratinases; Fig. 1 shows M. canis

Mycopathologia (2008) 166:267275

Fig. 1 Immunohistochemical detection of the keratinolytic

protease Sub3 in a skin section of a Microsporum canis naturally
infected cat. Sub3 was detected using a purified specific
polyclonal IgG. All the infected hair follicles are positive,
indicating the presence of Sub3 at this level (arrows), whereas
uninfected ones remain unlabeled. Bar corresponds to 50 lm

hyphae located in hair shafts and secreting Sub3. In

contrast, little information is available about other
hydrolases, such as lipases and a ceramidase, produced by these fungi [19, 20]. A direct relationship
between keratinases and pathogenicity was established by Viani et al. [21]. They showed that, unlike
for other hydrolases, M. canis strains with the highest
keratinolytic activities in vitro were responsible for
the more symptomatic infections; meanwhile, since
the more severe lesions also resolved faster, these
results raise the question whether keratinases or skin
damage they cause are linked with inflammation and
immunity.
The importance of dermatophytic keratinolytic
proteases for pathogenicity is thus well established.
Nevertheless, they cannot act before disulfide bridges
are reduced within the compact protein network that
constitutes keratinized tissues [22]. This was recently
shown to depend from a sulfite efflux pump encoded by
the Ssu1 gene [23]. Sulfite excretion by this transporter
allows sulfitolysis of proteins, rendering them accessible for proteases, and functions in the same time as a
possible detoxification pathway. It could therefore be a
target for new anti-fungal treatments.
Fungal-secreted proteases are produced at high
levels when the sole available carbon and nitrogen
source is made of complex proteins as opposed to
glucose or peptidic digests [4, 5, 24]. The mechanisms by which the expression of the corresponding
genes are induced or derepressed are not clearly
elucidated. Keratinolytic activity of dermatophytes is

269

probably induced, at least in part, by a restricted

supply of assimilable nutrients. The switch in gene
activation that would occur at this moment could be
controlled by a transcription factor from the GATA
family. Indeed, in many fungi, these zinc-finger
transcription factors induce the expression of a whole
series of genes in response to a change in nitrogen
source [25, 26]. Among these factors are the products
of the areA and nit-2 genes from Aspergillus nidulans
and Neurospora crassa, respectively; they induce the
production of numerous enzymes and permeases,
including extracellular proteases, conferring the ability to utilize a more complex substrate. Furthermore,
in several human and plant pathogenic fungi, areA/
nit-2-like genes have been incriminated in pathogenicity [2729]; however, this is not always the case
[30]. Recently, the equivalent of these genes in M.
canis, dnr1, was isolated and functionally investigated by gene disruption. Its inactivation led to
impaired growth when keratin was the sole nitrogen
source [31]. In T. rubrum, expression of endoproteases is upregulated by another zinc-finger
transcription factor, PACC, that is activated by
elevated pH. Disruption of the PACC gene hindered
both the secretion of keratinolytic activity and the
fungal growth on nail fragments as the sole substrate
[32]. Alternatively, Kaufman et al. [14] proposed that
constitutively expressed enzymes could release
inducers from host skin proteins.
To efficiently survive and grow in a particular
host, dermatophytes have to coordinate the expression of their numerous secreted proteases. The
protein and protease secretion profile of dermatophytes in an inducing medium greatly varies from
one species to another, despite the extremely high
homology degree between the corresponding orthologous genes [33]. The specialization of each species,
including the severity of inflammation induced in a
given host, could thus be related to differential
regulation of secreted protein expression.
Two genes coding for a thioredoxin and for a
cellulase homologue respectively, were identified as
putative T. mentagrophytes virulence factors owing
to their increased expression in a medium based on
skin extracellular matrix proteins [34]. Thioredoxin
was suggested to play a role in the activation of
fungal or host proteases, or in the defense against
oxidative stress; however, the role of these two
factors in pathogenicity remains hypothetical.

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It must finally be noted that skin damages upon

dermatophytic infection can result from other processes than direct action of fungal lytic enzymes.
Indeed, host proteases could possibly be activated
and participate in inducing lesions. Besides, profound
ultrastructural and functional changes are induced in
epidermal barrier upon T. rubrum infection [35].
These authors showed that the protein composition of
cornified envelope was notably altered, probably
under the influence of inflammation-associated factors, and that this alteration was associated with
reduced skin water-binding properties.

Facing Immune Response

Infections by dermatophytes induce a specific
immune response, with humoral and cellular components. It is now clear that the efficient and protective
response against dermatophytosis is a cell-mediated
response of the Delayed Type Hypersensitivity
(DTH), characterized namely by the action of macrophages as effector cells and by some key cytokines
like interferon-c (IFN-c). However, the immune
response that is raised, and especially the degree of
inflammation, varies according to the dermatophyte
species, to the host species, and to the pathophysiological status of the host. The different ways in
which dermatophytes may counter the immune
system, or induce damage via immune defenses, are
briefly described here. They include lymphocyte
inhibition by cell wall mannans, macrophage function
alteration, differential activation of keratinocytes and,
putatively, differential secretion of proteases.
As evoked above [21, 33], the pattern of proteases
secreted by dermatophytes might play an important
role in relation with immunity and inflammation. The
intensity of inflammatory reaction could simply
depend on the depth of skin damage caused by the
infection, damage that is probably largely determined
by proteases. Indeed, as suggested by Dahl and
Grando [36], weakly invasive dermatophyte species
could shelter from soluble or cellular components of
the immune system by remaining in the superficial
non-living skin layers. Secreted proteases may also
influence immune defenses by virtue of their specific
immunogenic properties, since some of them were
definitely shown to induce a specific immune
response. It is the case of a subtilisin (Sub3) and a

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metalloprotease (Mep3) from M. canis [3739];

however, the clinical status of naturally infected cats
could not be associated with a possible modulation of
the anti-Sub3 humoral response or of the humoral
response against a crude exoantigen containing
several proteases [40]. Two other dermatophyticsecreted proteases, a subtilisin from T. rubrum (Tri r
2) and the dipeptidyl-peptidase V from Trichophyton
tonsurans (Tri t 4), can induce dual immune
responses. Acute dermatophytosis is associated with
a DTH skin response against them, while persistent
disease corresponds to immediate hypersensitivity
(IH) responses, to high levels of IgE and IgG4
antibodies, and to the production of Th2 cytokines by
mononuclear leukocytes [4143]. A role as surface
antigen has also been proposed for the subtilisin Sub1
from T. rubrum [4]. Finally, some dermatophytic
secreted proteases can act directly on immune
mediators, as demonstrated for fungal DppIV [44].
Some dermatophytes, like T. rubrum and T. tonsurans, are highly adapted to humans and can evade or
silence the immune response, causing chronic dermatophytosis. Trichophyton rubrum cell wall mannans
(TRM) seem to be involved in an immunosuppression
phenomenon. In a dose-dependent manner, TRM are
able to inhibit in vitro lymphoproliferative response of
mononuclear leukocytes in response to several antigens (dermatophytic or not) and mitogens [45];
paradoxically, they are a major T-cell antigen [46].
Although specific suppressor T cells are eventually
activated during persistent infections [36], target cells
for TRM action appear to be monocytes rather then
lymphocytes [47]. TRM may also inhibit stratum
corneum turnover, directly or via lymphocyte function
alteration [48, 49]. The fine chemical structure of T.
rubrum and T. mentagrophytes mannans was further
characterized by Ikuta et al. [50], who pointed out
potentially significant differences when comparing
these to mannans from other fungal species. Moreover,
Blake et al. [51] indicated that the amount and
inhibitory properties of TRM were different from
those of other dermatophyte species. Despite these
numerous investigations, the mechanism underlying
immunomodulatory properties of TRM remains poorly
understood. This point was recently investigated by
Campos et al. [52], who suggested that the observed
inhibitory effect could simply result from the saturation
of mannose receptors at the surface of macrophages
and subsequent impairment of phagocytosis.

Mycopathologia (2008) 166:267275

The central role of both keratinocytes and monocytes/macrophages in the modulation of antidermatophyte response has otherwise been confirmed
and somewhat lightened. The level of interleukin
(IL)-1a produced by T. rubrum-treated keratinocytes
is significantly lower than that induced by T. mentagrophytes, which could be related to the different
clinical expression of the two types of infection [53].
Additionally, the low cytokine secretion from human
keratinocytes infected with T. tonsurans, in comparison with Arthroderma benhamiae, could account for
the weak inflammatory response induced by this
species in humans [54]. Macrophages are known to
be an important element of anti-dermatophyte
defenses [47, 53, 55]. In the study performed by
Campos et al. [52], the behavior of glass-attached
macrophages incubated with T. rubrum microconidia
was analyzed. After intracellular differentiation of
conidia into hyphae, cell membrane breaking
occurred, resulting in death of the macrophages.
Besides, while the secretion of the anti-inflammatory
cytokine IL-10 by macrophages was increased upon
infection, factors related to enhancement of the
relevant immune response were downregulated, i.e.
class II MHC, CD54 and CD80 costimulation molecules, nitric oxide, and Il-12. The production of
tumor necrosis factor (TNF-a), which is not normally
associated with immunosuppression, but can favor
intracellular growth of pathogens [56], was also
stimulated in infected macrophages. Trichophyton
rubrum could thus evade the immune response by
killing macrophages or modulating their activation
program.
The complex relationship existing between dermatophytosis and allergic diseases has to be evoked
here. The predisposing role of atopy in chronic
dermatophytosis is not clearly established; on the
other hand, it is now accepted that chronic dermatophytosis, associated with IH skin test reactions and
Th2 cytokines, can contribute to the pathogenesis of
allergic diseases, especially asthma [57]. This can be
explained in part by homing of T-cells from the skin
to the lungs, since Th2 cells activated by dermatophytic antigens may lack an important skin-homing
marker known as CLA (Cutaneous Lymphocyteassociated Antigen) [58]. Another possible link
between dermatophytosis and allergy is the delivery
of dermatophytic antigens to the lungs by circulating
antigen presenting cells (APCs) [57]. Furthermore, as

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stated above, dermatophytic enzymes could influence

the orientation of the immune response by cleaving
soluble immune factors. For instance, many biological peptides which mediate inflammation were
shown to be substrates for DppIV [59, 60].

New Tools for the Elucidation of Dermatophytic

Virulence Mechanisms
Functional investigation of the genomes of dermatophytes is a challenging task, hindered by several
technical difficulties. Transformation frequency is
low in dermatophytes [6163], and their possible
multinuclear structure is an additional hurdle to
transformation. Furthermore, homologous recombination in dermatophytes [62] as in other filamentous
fungi [64] is relatively inefficient. In spite of these
obstacles, gene disruption via homologous recombination has been attained in T. rubrum [32, 65] and
M. canis [31]. Alternatively, RNA interference technology [66] can be used to study gene functions in
dermatophytes. It has been successfully applied in
M. canis to down regulate the expression of genes
coding for two secreted proteases, Sub3 and DppIV
[67]. The greatest advantage of this method over gene
disruption is the possibility to inhibit several genes in
the same time, what would be particularly helpful to
investigate the large protease gene families from
dermatophytes. It was recently observed that a single
gene fragment was able to silence simultaneously two
members of the M. canis subtilisin family (unpublished data). The generation of expressed sequence
tags (ESTs) [68] and high-throughput methods
developed in T. rubrum for the analysis of transcriptomes, i.e. the use of cDNA microarrays [6971], and
for the analysis of secreted proteomes [20] could be
helpful to investigate host-fungus relationship.
The use of appropriate ex vivo or in vitro infection
models is necessary to understand the fine pathophysiological mechanisms of dermatophytosis.
Several ex vivo models have been used in this goal,
i.e. keratinocytes from the stratum corneum [79,
72], nail fragments [10, 73], hair follicles [74], and
skin explants as by-products from plastic surgery
[11]. They were associated with high-performance
microscopy technologies or with particular visualization methods like transformation with the Green
Fluorescent Protein (GFP) marker [63]. More

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sophisticated in vitro models have also been developed. Nakamura et al. [75] used keratinocytes
monolayers to study the cytokine production in
response to T. mentagrophytes infection, and Rashid
et al. [76] successfully developed a reconstructed
human epidermis (RHE) that was infected with the
same fungus. The in vitro model of RFE that was
recently developed in our laboratory [12] is currently
utilized to study the activation of feline keratinocytes
and feline dendritic cells, the precursors of Langerhans cells, by M. canis secreted proteases.

Conclusion
Pathogenesis of dermatophytosis can be investigated
from the fungal or from the host point of view;
nevertheless, both aspects are intimately linked. In
addition, pathophysiological mechanisms probably
vary according to fungal species and the host status.
Remarkably, the pattern of proteases secreted by
dermatophytes could underlie fungal survival on the
host and the clinical evolution of the infection, not
only by providing nutrients to the detriment of
keratinized barrier, but also by triggering and modulating the immune response.
Elucidation of the primary stimuli and intracellular
pathways that regulate proteases secretion is just
beginning, as is the understanding of dermatophytic
adhesion process. The strategies developed by dermatophytes like T. rubrum to evade or inhibit the
immune reaction are studied for a long time, but need
deeper characterization. Likewise, the way in which
keratinocytes are activated as immune mediators by
the fungus is likely to be pivotal and requires further
investigation.
To progress rapidly, research about pathogenesis
of dermatophytosis has to make use of both the
knowledge acquired from other fungal pathogens and
the new emerging tools that have been developed,
including genetic tools and sophisticated in vitro
infection models. This will undoubtedly expedite the
uncovering of the mechanisms underlying the infection process and, in fine, lead to the design of new
therapeutic approaches.
Acknowledgments We thank Prof. M. Monod (Dermatology
Service, Centre Hospitalier Universitaire Vaudois, Lausanne,
Switzerland) for careful reading over and advice.

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