Professional Documents
Culture Documents
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
123
268 Mycopathologia (2008) 166:267275
factors other than proteases. Most of these works are at 12 h, germination had started by 24 h, and
either describing the adhesion and invasion steps of penetration of the stratum corneum occurred after
infection, or dealing with immunosuppressive proper- 3 days. In our laboratory, adherence of M. canis
ties of Trichophyton rubrum. arthrospores was studied in a recently developed
When compared to most other fungal diseases, host- model of reconstructed feline epidermis (RFE) [12];
fungus relationship in dermatophytic infections is it was shown to begin by 2 h and to be still increasing
remarkable, in that these fungi affect immunocompe- by 6 h (unpublished data).
tent individuals, but generally invade only superficial Little is known about the factors that mediate
keratinized structures. Anthropophilic and zoophilic adherence of dermatophytes. The ability of T. rubrum
species are obligatory parasites. The clinical expres- to adhere to epithelial cells has been attributed to
sion of dermatophytosis strongly varies depending on carbohydrate-specific adhesins, expressed on the sur-
both the host and fungal species. Whereas infection face of microconidia [13]. From a morphological point
can be acute and rapidly eliminated through an of view, fibrillar projections have been observed in T.
efficient innate and specific immune response, some mentagrophytes during the adherence phase [9, 14]. At
dermatophyte species, e.g. T. rubrum and Microspo- the skin surface, long and sparse fibrils connect fungal
rum canis, reach a high degree of adaptation to their arthroconidia to keratinocytes and to each other, while
preferred host, and can cause chronic infections with in the inner skin layers, newly formed arthroconidia
little or no symptoms. These intriguing aspects of show thin and short appendices covering their entire
dermatophytic infections are still to be lightened. This surface; the latter begin to vanish as a large contact area
article intends to gather and summarize available data is established between conidia and skin tissue [14].
about the diverse fields of dermatophytosis pathogen- Based on the findings made in the yeast Candida
esis; in addition, it provides a general view of the albicans, where secreted aspartic proteases (Saps)
genetic tools and infection models that were recently have been shown to play a fundamental role in fungal
developed and that promise fast and accurate elucida- adherence to epithelia [1517], we formulated the
tion of dermatophytic infection processes. hypothesis that dermatophytic-secreted proteases
could facilitate or even be necessary for efficient
adherence. In that context, M. canis-secreted subtili-
Adhering to and Invading Superficial Skin Tissues sins, metalloproteases, and dipeptidyl-peptidases are
now being investigated as for their potential involve-
The kinetics of adherence to the skin or nail surface ment in adherence and early invasion steps, using our
was investigated in several Trichophyton and Micros- RFE model and several specific inhibitors such as
porum species, using different experimental models protein prosequences. The unique dipeptidyl-peptidase
and microscopy techniques. These studies showed a IV (DppIV) identified in Trichophyton spp. [6] and M.
time-dependent increase in the number of adhering canis (manuscript submitted) could also be involved in
spores, followed by germination and invasion of the the adhesion process, as previously demonstrated in
stratum corneum by hyphae growing in multiple Porphyromonas gingivalis [18]. Although this phe-
directions. Zurita and Hay [7] observed that maxi- nomenon is independent from enzymatic activity,
mum adherence of Trichophyton spp. arthroconidia to membrane-associated DppIV from this pathogenic
keratinocytes in suspension occurred within 34 h. bacterium mediates adherence to fibronectin.
Aljabre et al. [8, 9] used stripped sheets of stratum
corneum or separate keratinocytes to demonstrate that
adherence of Trichophyton mentagrophytes arthro- Growing on Hard Keratinized Substrates
conidia is maximum by 6 h and that germination of
these spores begins by 4 h. In a nail plate model, Dermatophytes are provided with an arsenal of
adherence and germination of T. mentagrophytes proteases aimed at the digestion of the keratin network
arthrospores were observed at 6 h and side branches into assimilable oligopeptides or amino acids. These
at 16 h [10]. The early stages of T. mentagrophytes fungi secrete multiple serine and metallo- endopro-
infection were investigated using skin explants of full teases (subtilisins and fungalysins, respectively) [25]
epidermis thickness [11]. Adherence was maximum formerly called keratinases; Fig. 1 shows M. canis
123
Mycopathologia (2008) 166:267275 269
123
270 Mycopathologia (2008) 166:267275
It must finally be noted that skin damages upon metalloprotease (Mep3) from M. canis [3739];
dermatophytic infection can result from other pro- however, the clinical status of naturally infected cats
cesses than direct action of fungal lytic enzymes. could not be associated with a possible modulation of
Indeed, host proteases could possibly be activated the anti-Sub3 humoral response or of the humoral
and participate in inducing lesions. Besides, profound response against a crude exoantigen containing
ultrastructural and functional changes are induced in several proteases [40]. Two other dermatophytic-
epidermal barrier upon T. rubrum infection [35]. secreted proteases, a subtilisin from T. rubrum (Tri r
These authors showed that the protein composition of 2) and the dipeptidyl-peptidase V from Trichophyton
cornified envelope was notably altered, probably tonsurans (Tri t 4), can induce dual immune
under the influence of inflammation-associated fac- responses. Acute dermatophytosis is associated with
tors, and that this alteration was associated with a DTH skin response against them, while persistent
reduced skin water-binding properties. disease corresponds to immediate hypersensitivity
(IH) responses, to high levels of IgE and IgG4
antibodies, and to the production of Th2 cytokines by
Facing Immune Response mononuclear leukocytes [4143]. A role as surface
antigen has also been proposed for the subtilisin Sub1
Infections by dermatophytes induce a specific from T. rubrum [4]. Finally, some dermatophytic
immune response, with humoral and cellular compo- secreted proteases can act directly on immune
nents. It is now clear that the efficient and protective mediators, as demonstrated for fungal DppIV [44].
response against dermatophytosis is a cell-mediated Some dermatophytes, like T. rubrum and T. tonsu-
response of the Delayed Type Hypersensitivity rans, are highly adapted to humans and can evade or
(DTH), characterized namely by the action of mac- silence the immune response, causing chronic dermat-
rophages as effector cells and by some key cytokines ophytosis. Trichophyton rubrum cell wall mannans
like interferon-c (IFN-c). However, the immune (TRM) seem to be involved in an immunosuppression
response that is raised, and especially the degree of phenomenon. In a dose-dependent manner, TRM are
inflammation, varies according to the dermatophyte able to inhibit in vitro lymphoproliferative response of
species, to the host species, and to the pathophysi- mononuclear leukocytes in response to several anti-
ological status of the host. The different ways in gens (dermatophytic or not) and mitogens [45];
which dermatophytes may counter the immune paradoxically, they are a major T-cell antigen [46].
system, or induce damage via immune defenses, are Although specific suppressor T cells are eventually
briefly described here. They include lymphocyte activated during persistent infections [36], target cells
inhibition by cell wall mannans, macrophage function for TRM action appear to be monocytes rather then
alteration, differential activation of keratinocytes and, lymphocytes [47]. TRM may also inhibit stratum
putatively, differential secretion of proteases. corneum turnover, directly or via lymphocyte function
As evoked above [21, 33], the pattern of proteases alteration [48, 49]. The fine chemical structure of T.
secreted by dermatophytes might play an important rubrum and T. mentagrophytes mannans was further
role in relation with immunity and inflammation. The characterized by Ikuta et al. [50], who pointed out
intensity of inflammatory reaction could simply potentially significant differences when comparing
depend on the depth of skin damage caused by the these to mannans from other fungal species. Moreover,
infection, damage that is probably largely determined Blake et al. [51] indicated that the amount and
by proteases. Indeed, as suggested by Dahl and inhibitory properties of TRM were different from
Grando [36], weakly invasive dermatophyte species those of other dermatophyte species. Despite these
could shelter from soluble or cellular components of numerous investigations, the mechanism underlying
the immune system by remaining in the superficial immunomodulatory properties of TRM remains poorly
non-living skin layers. Secreted proteases may also understood. This point was recently investigated by
influence immune defenses by virtue of their specific Campos et al. [52], who suggested that the observed
immunogenic properties, since some of them were inhibitory effect could simply result from the saturation
definitely shown to induce a specific immune of mannose receptors at the surface of macrophages
response. It is the case of a subtilisin (Sub3) and a and subsequent impairment of phagocytosis.
123
Mycopathologia (2008) 166:267275 271
The central role of both keratinocytes and mono- stated above, dermatophytic enzymes could influence
cytes/macrophages in the modulation of anti- the orientation of the immune response by cleaving
dermatophyte response has otherwise been confirmed soluble immune factors. For instance, many biolog-
and somewhat lightened. The level of interleukin ical peptides which mediate inflammation were
(IL)-1a produced by T. rubrum-treated keratinocytes shown to be substrates for DppIV [59, 60].
is significantly lower than that induced by T. ment-
agrophytes, which could be related to the different
clinical expression of the two types of infection [53]. New Tools for the Elucidation of Dermatophytic
Additionally, the low cytokine secretion from human Virulence Mechanisms
keratinocytes infected with T. tonsurans, in compar-
ison with Arthroderma benhamiae, could account for Functional investigation of the genomes of dermato-
the weak inflammatory response induced by this phytes is a challenging task, hindered by several
species in humans [54]. Macrophages are known to technical difficulties. Transformation frequency is
be an important element of anti-dermatophyte low in dermatophytes [6163], and their possible
defenses [47, 53, 55]. In the study performed by multinuclear structure is an additional hurdle to
Campos et al. [52], the behavior of glass-attached transformation. Furthermore, homologous recombi-
macrophages incubated with T. rubrum microconidia nation in dermatophytes [62] as in other filamentous
was analyzed. After intracellular differentiation of fungi [64] is relatively inefficient. In spite of these
conidia into hyphae, cell membrane breaking obstacles, gene disruption via homologous recombi-
occurred, resulting in death of the macrophages. nation has been attained in T. rubrum [32, 65] and
Besides, while the secretion of the anti-inflammatory M. canis [31]. Alternatively, RNA interference tech-
cytokine IL-10 by macrophages was increased upon nology [66] can be used to study gene functions in
infection, factors related to enhancement of the dermatophytes. It has been successfully applied in
relevant immune response were downregulated, i.e. M. canis to down regulate the expression of genes
class II MHC, CD54 and CD80 costimulation mol- coding for two secreted proteases, Sub3 and DppIV
ecules, nitric oxide, and Il-12. The production of [67]. The greatest advantage of this method over gene
tumor necrosis factor (TNF-a), which is not normally disruption is the possibility to inhibit several genes in
associated with immunosuppression, but can favor the same time, what would be particularly helpful to
intracellular growth of pathogens [56], was also investigate the large protease gene families from
stimulated in infected macrophages. Trichophyton dermatophytes. It was recently observed that a single
rubrum could thus evade the immune response by gene fragment was able to silence simultaneously two
killing macrophages or modulating their activation members of the M. canis subtilisin family (unpub-
program. lished data). The generation of expressed sequence
The complex relationship existing between der- tags (ESTs) [68] and high-throughput methods
matophytosis and allergic diseases has to be evoked developed in T. rubrum for the analysis of transcript-
here. The predisposing role of atopy in chronic omes, i.e. the use of cDNA microarrays [6971], and
dermatophytosis is not clearly established; on the for the analysis of secreted proteomes [20] could be
other hand, it is now accepted that chronic dermat- helpful to investigate host-fungus relationship.
ophytosis, associated with IH skin test reactions and The use of appropriate ex vivo or in vitro infection
Th2 cytokines, can contribute to the pathogenesis of models is necessary to understand the fine patho-
allergic diseases, especially asthma [57]. This can be physiological mechanisms of dermatophytosis.
explained in part by homing of T-cells from the skin Several ex vivo models have been used in this goal,
to the lungs, since Th2 cells activated by dermato- i.e. keratinocytes from the stratum corneum [79,
phytic antigens may lack an important skin-homing 72], nail fragments [10, 73], hair follicles [74], and
marker known as CLA (Cutaneous Lymphocyte- skin explants as by-products from plastic surgery
associated Antigen) [58]. Another possible link [11]. They were associated with high-performance
between dermatophytosis and allergy is the delivery microscopy technologies or with particular visuali-
of dermatophytic antigens to the lungs by circulating zation methods like transformation with the Green
antigen presenting cells (APCs) [57]. Furthermore, as Fluorescent Protein (GFP) marker [63]. More
123
272 Mycopathologia (2008) 166:267275
123
Mycopathologia (2008) 166:267275 273
16. Monod M, Borg-von Zepelin M. Secreted aspartic prote- 31. Yamada T, Makimura K, Abe S. Isolation, characteriza-
ases as virulence factors of Candida species. Biol Chem. tion, and disruption of dnr1, the areA/nit-2-like nitrogen
2002;383:108793. regulatory gene of the zoophilic dermatophyte, Microspo-
17. De Bernardis F, Liu H, OMahony R, La Valle R, Bar- rum canis. Med Mycol. 2006;44:24352.
tollino S, Sandini S, Grant S, Brewis N, Tomlinson I, 32. Ferreira-Nozawa MS, Silveira HC, Ono CJ, Fachin AL,
Basset RC, Holton J, Roitt IM, Cassone A. Human domain Rossi A, Martinez-Rossi NM. The pH signaling tran-
antibodies against virulence traits of Candida albicans scription factor PacC mediates the growth of Trichophyton
inhibit fungus adherence to vaginal epithelium and protect rubrum on human nail in vitro. Med Mycol. 2006;44:641
against experimental vaginal candidiasis. J Infect Dis. 5.
2007;195:14957. 33. Giddey K, Favre B, Quadroni M, Monod M. Closely
18. Kumagai Y., Yagishita H., Yajima A., Okamoto T., related dermatophyte species produce different patterns of
Konishi K. Molecular mechanism for connective tissue secreted proteins. FEMS Microbiol Lett. 2007;267:95101.
destruction by dipeptidyl aminopeptidase IV produced by 34. Kaufman G, Berdicevsky I, Woodfolk JA, Horwitz BA.
the periodontal pathogen Porphyromonas gingivalis. Infect Markers for host-induced gene expression in Trichophyton
Immun. 2005;73:265564. dermatophytosis. Infect Immun. 2005;73:658490.
19. Hellgren L, Vincent J. Lipolytic activity of some derma- 35. Jensen JM, Pfeiffer S, Akaki T, Schroder JM, Kleine M,
tophytes. II. Isolation and characterisation of the lipase of Neumann C, Proksch E, Brasch J. Barrier function, epi-
Epidermophyton floccosum. J Med Microbiol. dermal differentiation, human beta-defensin 2 expression
1981;14:34750. in tinea corporis. J Invest Dermatol. 2007;127:17207.
20. Giddey K, Monod M, Barblan J, Potts A, Waridel P, Zaugg 36. Dahl MV, Grando SA. Chronic dermatophytosis: what is
C, Quadroni M. Comprehensive analysis of proteins special about Trichophyton rubrum? Adv Dermatol.
secreted by Trichophyton rubrum and Trichophyton vio- 1994;9:97109;discussion 1101.
laceum under in vitro conditions. J Proteome Res. 37. Brouta F, Descamps F, Vermout S, Monod M, Losson B,
2007;6:308192. Mignon B. Humoral and cellular immune response to a
21. Viani FC, Dos Santos JI, Paula CR, Larson CE, Gambale Microsporum canis recombinant keratinolytic metallopro-
W. Production of extracellular enzymes by Microsporum tease (r-MEP3) in experimentally infected guinea pigs.
canis and their role in its virulence. Med Mycol. Med Mycol. 2003;41:495501.
2001;39:4638. 38. Descamps F, Brouta F, Vermout S, Monod M, Losson B,
22. Kunert J. Effect of reducing agents on proteolytic and Mignon B. Recombinant expression and antigenic prop-
keratinolytic activity of enzymes of Microsporum gypse- erties of a 31.5-kDa keratinolytic subtilisin-like serine
um. Mycoses. 1992;35:3438. protease from Microsporum canis. FEMS Immunol Med
23. Lechenne B, Reichard U, Zaugg C, Fratti M, Kunert J, Microbiol. 2003;38:2934.
Boulat O, Monod M. Sulphite efflux pumps in Aspergillus 39. Mignon BR, Leclipteux T, Focant C, Nikkels AJ, Pierard
fumigatus and dermatophytes. Microbiology. GE, Losson BJ. Humoral and cellular immune response to
2007;153:90513. a crude exo-antigen and purified keratinase of Microspo-
24. Mignon B, Swinnen M, Bouchara JP, Hofinger M, Nikkels rum canis in experimentally infected guinea pigs. Med
A, Pierard G, Gerday C, Losson B. Purification and char- Mycol. 1999;37:1239.
acterization of a 31.5 kDa keratinolytic subtilisin-like 40. Mignon BR, Coignoul F, Leclipteux T, Focant C, Losson
serine protease from Microsporum canis and evidence of BJ. Histopathological pattern and humoral immune
its secretion in naturally infected cats. Med Mycol. response to a crude exo-antigen and purified keratinase of
1998;36:395404. Microsporum canis in symptomatic and asymptomatic
25. Marzluf GA. Genetic regulation of nitrogen metabolism in infected cats. Med Mycol. 1999;37:19.
the fungi. Microbiol Mol Biol Rev. 1997;61:1732. 41. Woodfolk JA, Platts-Mills TA. Diversity of the human
26. Scazzocchio C. The fungal GATA factors. Curr Opin allergen-specific T cell repertoire associated with distinct
Microbiol. 2000;3:12631. skin test reactions: delayed-type hypersensitivity-associ-
27. Hensel M, Arst HN Jr, Aufauvre-Brown A, Holden DW. ated major epitopes induce Th1- and Th2-dominated
The role of the Aspergillus fumigatus areA gene in invasive responses. J Immunol. 2001;167:54129.
pulmonary aspergillosis. Mol Gen Genet. 1998;258:553 42. Woodfolk JA, Sung SS, Benjamin DC, Lee JK, Platts-Mills
57. TA. Distinct human T cell repertoires mediate immediate
28. Limjindaporn T, Khalaf RA, Fonzi WA. Nitrogen metab- and delayed-type hypersensitivity to the Trichophyton
olism and virulence of Candida albicans require the antigen, Tri r 2. J Immunol. 2000;165:437987.
GATA-type transcriptional activator encoded by GAT1. 43. Woodfolk JA, Wheatley LM, Piyasena RV, Benjamin DC,
Mol Microbiol. 2003;50:9931004. Platts-Mills TA. Trichophyton antigens associated with IgE
29. Pellier AL, Lauge R, Veneault-Fourrey C, Langin T. antibodies and delayed type hypersensitivity. Sequence
CLNR1, the AREA/NIT2-like global nitrogen regulator of homology to two families of serine proteinases. J Biol
the plant fungal pathogen Colletotrichum lindemuthianum Chem. 1998;273:2948996.
is required for the infection cycle. Mol Microbiol. 44. Beauvais A, Monod M, Wyniger J, Debeaupuis JP,
2003;48:63955. Grouzmann E, Brakch N, Svab J, Hovanessian AG, Latge
30. Froeliger EH, Carpenter BE. NUT1, a major nitrogen JP. Dipeptidyl-peptidase IV secreted by Aspergillus fu-
regulatory gene in Magnaporthe grisea, is dispensable for migatus, a fungus pathogenic to humans. Infect Immun.
pathogenicity. Mol Gen Genet. 1996;251:64756. 1997;65:30427.
123
274 Mycopathologia (2008) 166:267275
45. Blake JS, Dahl MV, Herron MJ, Nelson RD. An immun- Lacroix JS. Implication of dipeptidylpeptidase IV activity
oinhibitory cell wall glycoprotein (mannan) from in human bronchial inflammation and in bronchoconstric-
Trichophyton rubrum. J Invest Dermatol. 1991;96:65761. tion evaluated in anesthetized rabbits. Respiration.
46. MacCarthy KG, Blake JS, Johnson KL, Dahl MV, Kalish 2008;75:8997.
RS. Human dermatophyte-responsive T-cell lines recog- 61. Gonzalez R, Ferrer S, Buesa J, Ramon D. Transformation
nize cross-reactive antigens associated with mannose-rich of the dermatophyte Trichophyton mentagrophytes to hy-
glycoproteins. Exp Dermatol. 1994;3:6671. gromycin B resistance. Infect Immun. 1989;57:29235.
47. Grando SA, Hostager BS, Herron MJ, Dahl MV, Nelson 62. Yamada T, Makimura K, Uchida K, Yamaguchi H.
RD. Binding of Trichophyton rubrum mannan to human Reproducible genetic transformation system for two der-
monocytes in vitro. J Invest Dermatol. 1992;98:87680. matophytes, Microsporum canis and Trichophyton
48. Grando SA, Herron MJ, Dahl MV, Nelson RD. Binding mentagrophytes. Med Mycol. 2005;43:53344.
and uptake of Trichophyton rubrum mannan by human 63. Kaufman G, Horwitz BA, Hadar R, Ullmann Y, Ber-
epidermal keratinocytes: a time-course study. Acta Derm dicevsky I. Green fluorescent protein (GFP) as a vital
Venereol. 1992;72:2736. marker for pathogenic development of the dermatophyte
49. Dahl MV. Suppression of immunity and inflammation by Trichophyton mentagrophytes. Microbiology. 2004;150:
products produced by dermatophytes. J Am Acad Derma- 278590.
tol. 1993;28:S19-23. 64. Ruiz-Diez B. Strategies for the transformation of fila-
50. Ikuta K, Shibata N, Blake JS, Dahl MV, Nelson RD, Hisa- mentous fungi. J Appl Microbiol. 2002;92:18995.
michi K, Kobayashi H, Suzuki S, Okawa Y. NMR study of 65. Fachin AL, Ferreira-Nozawa MS, Maccheroni W Jr,
the galactomannans of Trichophyton mentagrophytes and Martinez-Rossi NM. Role of the ABC transporter TruM-
Trichophyton rubrum. Biochem J. 1997;323:297305. DR2 in terbinafine, 4-nitroquinoline N-oxide and ethidium
51. Blake JS, Cabrera RC, Dahl MV, Herron MJ, Nelson RD. bromide susceptibility in Trichophyton rubrum. J Med
Comparison of the immunoinhibitory properties of cell Microbiol. 2006;55:10939.
wall mannan glycoproteins from Trichophyton rubrum and 66. Nakayashiki H. RNA silencing in fungi: mechanisms and
Microsporum canis [abstract]. J Invest Dermatol. 1991;96: applications. FEBS Lett. 2005;579:59507.
601. 67. Vermout S, Tabart T, Baldo A, Monod M, Losson B,
52. Campos MR, Russo M, Gomes E, Almeida SR. Stimula- Mignon B. RNA silencing in the dermatophyte Micros-
tion, inhibition and death of macrophages infected with porum canis. FEMS Microbiol Lett. 2007;275:3845.
Trichophyton rubrum. Microbes Infect. 2006;8:3729. 68. Wang L, Ma L, Leng W, Liu T, Yu L, Yang J, Yang L,
53. Ogawa H, Summerbell RC, Clemons KV, Koga T, Ran Zhang W, Zhang Q, Dong J, Xue Y, Zhu Y, Xu X, Wan Z,
YP, Rashid A, Sohnle PG, Stevens DA, Tsuboi R. Der- Ding G, Yu F, Tu K, Li Y, Li R, Shen Y, Jin Q. Analysis of
matophytes and host defence in cutaneous mycoses. Med the dermatophyte Trichophyton rubrum expressed
Mycol. 1998;36(Suppl 1):16673. sequence tags. BMC Genomics. 2006;7:255.
54. Shiraki Y, Ishibashi Y, Hiruma M, Nishikawa A, Ikeda S. 69. Zhang W, Yu L, Leng W, Wang X, Wang L, Deng X,
Cytokine secretion profiles of human keratinocytes during Yang J, Liu T, Peng J, Wang J, Li S, Jin Q. cDNA
Trichophyton tonsurans and Arthroderma benhamiae microarray analysis of the expression profiles of Tricho-
infections. J Med Microbiol. 2006;55:117585. phyton rubrum in response to novel synthetic fatty acid
55. Koga T, Duan H, Urabe K, Furue M. Immunohistochem- synthase inhibitor PHS11A. Fungal Genet Biol.
ical detection of interferon-gamma-producing cells in 2007;44:125261.
dermatophytosis. Eur J Dermatol. 2001;11:1057. 70. Yu L, Zhang W, Wang L, Yang J, Liu T, Peng J, Leng W,
56. Engele M, Stossel E, Castiglione K, Schwerdtner N, Chen L, Li R, Jin Q. Transcriptional profiles of the
Wagner M, Bolcskei P, Rollinghoff M, Stenger S. Induc- response to ketoconazole and amphotericin B in Tricho-
tion of TNF in human alveolar macrophages as a potential phyton rubrum. Antimicrob Agents Chemother.
evasion mechanism of virulent Mycobacterium tuberculo- 2007;51:14453.
sis. J Immunol. 2002;168:132837. 71. Liu T, Zhang Q, Wang L, Yu L, Leng W, Yang J, Chen L,
57. Woodfolk JA. Allergy and dermatophytes. Clin Microbiol Peng J, Ma L, Dong J, Xu X, Xue Y, Zhu Y, Zhang W,
Rev. 2005;18:3043. Yang L, Li W, Sun L, Wan Z, Ding G, Yu F, Tu K, Qian Z,
58. Ludwig RJ, Woodfolk JA, Grundmann-Kollmann M, En- Li R, Shen Y, Li Y, Jin Q. The use of global transcriptional
zensberger R, Runne U, Platts-Mills TA, Kaufmann R, analysis to reveal the biological and cellular events
Zollner TM. Chronic dermatophytosis in lamellar ichthy- involved in distinct development phases of Trichophyton
osis: relevance of a T-helper 2-type immune response to rubrum conidial germination. BMC Genomics.
Trichophyton rubrum. Br J Dermatol. 2001;145:51821. 2007;8:100.
59. Grouzmann E, Monod M, Landis B, Wilk S, Brakch N, 72. Smijs TG, Bouwstra JA, Schuitmaker HJ, Talebi M, Pavel
Nicoucar K, Giger R, Malis D, Szalay-Quinodoz I, Cava- S. A novel ex vivo skin model to study the susceptibility of
das C, Morel DR, Lacroix JS. Loss of dipeptidylpeptidase the dermatophyte Trichophyton rubrum to photodynamic
IV activity in chronic rhinosinusitis contributes to the treatment in different growth phases. J Antimicrob Che-
neurogenic inflammation induced by substance P in the mother. 2007;59:43340.
nasal mucosa. FASEB J. 2002;16:11324. 73. Rashid A, Scott EM, Richardson MD. Inhibitory effect of
60. Landis BN, Grouzmann E, Monod M, Busso N, Petak F, terbinafine on the invasion of nails by Trichophyton
Spiliopoulos A, Robert JH, Szalay-Quinodoz I, Morel DR, mentagrophytes. J Am Acad Dermatol. 1995;33:71823.
123
Mycopathologia (2008) 166:267275 275
74. Rashid A, Hodgins MB, Richardson MD. An in vitro human epidermal keratinocytes induced by Trichophyton
model of dermatophyte invasion of the human hair follicle. mentagrophytes. Clin Diagn Lab Immunol. 2002;9:9357.
J Med Vet Mycol. 1996;34:3742. 76. Rashid A, Edward M, Richardson MD. Activity of terbi-
75. Nakamura Y, Kano R, Hasegawa A, Watanabe S. Inter- nafine on Trichophyton mentagrophytes in a human living
leukin-8 and tumor necrosis factor alpha production in skin equivalent model. J Med Vet Mycol. 1995;33:22933.
123