COMMENTARY

FLG2 gene. Am J Med Genet A 2017;173: Margolis DJ, Gupta J, Apter AJ, Hoffstad O, types of infections, dermatophytosis
3201e4. Papadopoulos M, Rebbeck TR, et al. Exome
research is limited. This may be due to
Bolling MC, Jan SZ, Pasmooij AMG, sequencing of filaggrin and related genes in
African-American children with atopic derma- the usually mild course and low mor-
Lemmink HH, Franke LH, Yenamandra VK,
et al. Generalized ichthyotic peeling skin syn- titis. J Invest Dermatol 2014b;134:2272e4. tality associated with the disease, but the
drome due to FLG2 mutations. J Invest Der- Mohamad J, Sarig O, Godsel LM, Peled A, lack of suitable model systems to study
matol 2018;138:1881e4. Malchin N, Bochner R, et al. Filaggrin 2 defi- the disease may also be a factor.
Haftek M. Epidermal barrier disorders and cor- ciency results in abnormal cell-cell adhesion in Burstein et al. (2018) present a novel
neodesmosome defects. Cell Tissue Res the cornified cell layers and causes peeling
skin syndrome type A. J Invest Dermatol experimental model of epicutaneous
2015;360:483e90.
2018;138:1736e43. M. canis infection in mice. Application
Hansmann B, Schröder J-M, Gerstel U. Skin-derived
C-terminal filaggrin-2 fragments are Pseudomonas Pendaries V, Le Lamer M, Cau L, Hansmann B, of the fungus to the shaved and lightly
aeruginosaedirected antimicrobials targeting Malaisse J, Kezic S, et al. In a three-dimensional abraded back skin of wild-type C57BL/
bacterial replication. PLoS Pathog 2015;11: reconstructed human epidermis filaggrin-2 is 6 mice caused mild cutaneous lesions
e1005159. essential for proper cornification. Cell Death
Dis 2015;6:e1656. that resembled dermatophytosis in
Hsu C-Y, Henry J, Raymond A-A, Méchin M-C,
Samuelov L, Sprecher E. Peeling off the genetics of
humans. Macroscopic and histopatho-
Pendaries V, Nassar D, et al. Deimination
of human filaggrin-2 promotes its proteolysis by atopic dermatitis-like congenital disorders. logical examination showed erythema,
calpain 1. J Biol Chem 2011;286:23222e33. J Allergy Clin Immunol 2014;134:808e15. scaling, acanthosis, micro-abscesses,
Margolis DJ, Gupta J, Apter AJ, Ganguly T, Wu Z, Hansmann B, Meyer-Hoffert U, Gläser R, and some infiltration of neutrophilic
Hoffstad O, Papadopoulos M, et al. Filaggrin-2 Schröder J-M. Molecular identification and granulocytes. M. canis was recovered
variation is associated with more persistent expression analysis of filaggrin-2, a member of
atopic dermatitis in African American subjects. the S100 fused-type protein family. PLoS One from the lesions, with a peak of infec-
J Allergy Clin Immunol 2014a;133:784e9. 2009;4:e5227. tion at approximately 1 week and sub-
sequent clearance. This novel
dermatophytosis model is the first of
its kind, and it sets the stage
See related article on pg 1744 for investigating dermatophyte-host in-
teractions and protective mechanisms
against M. canis in skin in vivo.
IL-17 Takes Center Stage Burstein et al. (2018) observed a se-
lective induction of Microsporum-
in Dermatophytosis specific T helper (Th) type 17 cells after
infection. They further showed that the
Florian Sparber1 and Salomé LeibundGut-Landmann1 IL-17 pathway was responsible for
preventing uncontrolled fungal growth
The cytokine IL-17 plays a critical role in host defense against fungal infections.
and overt inflammation in response to
So far, clinical relevance for IL-17 antifungal activity focused on mucocutaneous
M. canis. During experimental derma-
candidiasis. Burstein and colleagues now provide evidence that type 17 immu-
tophytosis, increased fungal counts
nity is also essential for defense against dermatophytosis.
were detected in the skin of infected
Journal of Investigative Dermatology (2018) 138, 1691e1693. doi:10.1016/j.jid.2018.03.1518 mice that were deficient in the IL-17
receptor subunit A (IL-17RA) and in
mice that lacked IL-17A and IL-17F
Dermatophytoses, also termed ring- invasive infections. Among the kerati- cytokines. This is the first direct
worm or tinea, are among the most nophilic fungi that infect the skin, hair, demonstration of the relevance of type
frequent fungal infections in humans and nails, Microsporum canis is one of 17 immunity in dermatophytosis. These
(Brown et al., 2012) and in animals, the most prevalent species that cause important findings are supported by
affecting both pets and livestock dermatophytosis (Ghannoum and recent observations in the literature that
(Chermette et al., 2008). Clinical man- Isham, 2009). Infections are acquired hinted at a contribution of IL-17 in
ifestations of dermatophytosis include by contact with infected humans or human dermatophytosis (Alves de
alopecia, erythema, scaling, and, animals or from exposure to contami- Medeiros et al., 2016; Lanternier
rarely, pruritus. Although symptoms are nated soil or fomites. et al., 2013; Nielsen et al., 2015;
usually mild, the high frequency, zoo- Despite the worldwide clinical Sakuragi et al., 2016).
notic potential, and contagiousness of importance of dermatophytosis, disease IL-17 is well known to mediate host
dermatophytosis make the disease a pathogenesis and host responses to der- defense against other fungal infections
significant public health concern. matophytes remains poorly understood. in barrier tissues, in particular those
Moreover, in immunocompromised in- Even among fungal infections, which are caused by Candida species. This is
dividuals, dermatophytes can cause generally less well studied than other evidenced most strikingly by patients
with inborn errors in the IL-17
1
Section of Immunology, Vetsuisse Faculty, University of Zürich, Zürich, Switzerland
pathway that lead to increased sus-
Correspondence: Salomé LeibundGut-Landmann Section of Immunology, Vetsuisse Faculty, University
ceptibility to chronic mucocutaneous
of Zürich, Winterthurerstrasse 266a, CH-8057 Zürich, Switzerland E-mail: salome. candidiasis (CMC) (Li et al., 2017).
leibundgut-landmann@uzh.ch The novel link between dermatophy-
ª 2018 The Authors. Published by Elsevier, Inc. on behalf of the Society for Investigative Dermatology. tosis and the IL-17 pathway

www.jidonline.org 1691
 COMMENTARY
The results of Burstein et al. (2018)
Clinical Implications regarding the role of IL-17 in epicuta-
 Epicutaneous infection of mice with Microsporum canis provides an innova- neous M. canis infection parallels
tive model to investigate the pathogenesis of, and the host response to, what is currently known about IL-17
dermatophytosis. immunity in the context of superficial
infections with Candida albicans
 IL-17A and IL-17F protect from uncontrolled fungal growth during (Sparber and LeibundGut-Landmann,
dermatophytosis. 2015). Langerinþ dendritic cells were
 IL-17 signaling suppresses type 1 immunity to Microsporum canis, relieving found to contribute critically to the
inhibition of fungal clearance. regulation of the M. canis-specific
Th17 response (Burstein et al., 2018),
reminiscent of what was reported for
Th17 induction in response to epi-
established by Burstein et al. (2018) also lead to other uncommon invasive cutaneous infection with C. albicans
suggests that IL-17 deficiency might forms of fungal diseases, such as (Igyarto et al., 2011). Burstein et al.
render patients more susceptible to Candida encephalitis, extrapulmonary analyzed Th17 induction in the skin-
dermatophytosis in addition to aspergillosis, and phaeohyphomycosis draining lymph nodes in M. canis-
Candida. So far, primary immunode- (Li et al., 2017). Although reduced infected mice. It can be assumed that
ficiency patients with congenital de- Th17 responses were observed in some fungus-specific effector T cells migrate
fects in the IL-17 pathway have not CARD9-deficient patients, the defect in to sites of infection for local cytokine
been reported to display increased the IL-17 response may not be the only production. Whether other (innate)
prevalence of dermatophytosis (Li cause of disease manifestation in these cell types also contribute to IL-17
et al., 2017). However, the very patients. Neutrophil recruitment defects production in M. canis-infected skin,
small number of cases described to were identified as a leading cause of as was shown to be the case in other
date may obscure possibly increased Candida encephalitis and extrapulmo- models of superficial fungal infections
risk for dermatophytosis in those nary aspergillosis as a result of CARD9 (Sparber and LeibundGut-Landmann,
patients. deficiency (Li et al., 2017). It remains to 2015), awaits further investigation.
Rare cases of deep dermatophytosis be determined if the same applies in The observation by Burstein et al. that
were associated with genetic defects in deep dermatophytosis, where neutro- M. canis fungal burden was not
the innate signaling adaptor CARD9 (Li phils also make part of the dermal affected by the reduction of the
et al., 2017). CARD9 deficiency can lesions. fungus-specific Th17 population in

Figure 1. The proposed role of type 17 immunity in defense against M. canis in experimental dermatophytosis. IL-17A and IL-17F prevent fungal overgrowth
and antagonize a non-protective type-1 immune response in the skin. Epid., epidermis; SC, stratum corneum; Th, T helper.

1692 Journal of Investigative Dermatology (2018), Volume 138


absence of Langerinþ dendritic cells
points toward the involvement of
alternative cellular source(s) of IL-17
for infection control.
IL-17 limits the overgrowth of
M. canis and C. albicans in epithelial
barriers (Burstein et al., 2018; Sparber
and LeibundGut-Landmann, 2015).
However, the IL-17 pathway is not
relevant for limiting dissemination of
either pathogen to deeper tissues,
because no fungi were observed in
deeper layers of the skin (Burstein et al.,
2018; Igyarto et al., 2011) or the
mucosa in the case of oropharyngeal
candidiasis (Sparber and LeibundGut-
Landmann, 2015). Moreover, defi-
ciency in IL-17 signaling did not affect
the recruitment of neutrophils to sites
of infection in either dermatophytosis
(Burstein et al., 2018) or oropharyn-
geal candidiasis (Sparber and
LeibundGut-Landmann 2015). This
indicates that IL-17 immunity and
neutrophil accumulation are uncou-
pled and contribute independently of
each other to antifungal defense in
barrier tissues. The results from Bur-
stein et al. indicated that IL-17 may
mediate protection against M. canis by
enhancing epithelial barrier function
(Burstein et al., 2018). They observed
a thickened epidermis in wild-type,
but not in IL-17RAedeficient, mice
upon infection. Whether IL-17 also
acts via augmented production of
antimicrobial peptides that exert anti-
fungal activity, as was suggested to be
the case in the context of superficial
candidiasis, has not yet been
addressed.
Burstein et al. (2018) also provide ev-
idence for an alternative mechanism by
which IL-17 regulates antifungal immu-
nity in M. canis-infected skin (Figure 1).
They observed a shift in the balance of
IL-17e and IFN-geproducing T cells
in IL-17RA deficient mice. Targeting
IFN-g during infection reversed
fungal overgrowth, indicating that
IFN-g actively suppressed the control
of M. canis in the absence of a func-
tional IL-17 pathway. Whether a
similar mechanism applies during
CMC in primary immunodeficiency
patients with defects in IL-17 immu-
nity is unclear. Among the few studies
that assessed Th1 immunity in CMC
patients, the majority reported no
change or even a decrease in IFN-
geproducing cells, although at least
two studies reported enhanced Th1
responses (Baris et al., 2016;
Martinez-Martinez et al., 2015).
How, in the absence of a functional
IL-17 pathway, dysregulated Th1
immunity might interfere with fungal
control, in particular with the control of
M. canis, remains currently unknown.
This represents an important question to
be addressed in the future.
In summary, Burstein et al. (2018)
clearly identify IL-17 immunity as a
key mechanism of host defense against
the dermatophyte M. canis in mice.
Thus, IL-17 is a more common medi-
ator of antifungal immunity against
fungal pathogens, and its actions are
not limited to protection against
Candida as earlier work might have
suggested. Whether IL-17 is also
involved in host protection against
other fungi in mammalian barrier tis-
sues, such as the pathogenic dermato-
phyte Trichophyton or the skin
commensal yeast Malassezia, remains
to be determined.
CONFLICT OF INTEREST
The authors state no conflict of interest.
REFERENCES
Alves de Medeiros AK, Lodewick E, Bogaert DJ,
Haerynck F, Van Daele S, Lambrecht B, et al.
Chronic and invasive fungal infections in a
family with CARD9 deficiency. J Clin Immunol
2016;36:204e9.
COMMENTARY
Baris S, Alroqi F, Kiykim A, Karakoc-Aydiner E,
Ogulur I, Ozen A, et al. Severe early-onset
combined immunodeficiency due to heterozy-
gous gain-of-function mutations in STAT1.
J Clin Immunol 2016;36:641e8.
Brown GD, Denning DW, Gow NA, Levitz SM,
Netea MG, White TC. Hidden killers: human
fungal infections. Sci Transl Med 2012;4(165):
165rv13.
Burstein VL, Cuasconi L, Beccacece I,
Theumuer MG, Mena C, Prinz I, et al.
IL-17—mediated immunity controls skin
infection and T helper 1 response during
experimental Microsporum canis dermato-
phytosis. J Invest Dermatol 2018;138:
1744e53.
Chermette R, Ferreiro L, Guillot J. Dermatophytoses
in animals. Mycopathologia 2008;166(5e6):
385e405.
Ghannoum MA, Isham NC. Dermatophytes and
dermatophytoses. In: Anaissie EJ, McGinnis MR,
Pfaller MA, editors. Clinical mycology. Amster-
dam: Elsevier; 2009. p. 375e84.
Igyarto BZ, Haley K, Ortner D, Bobr A, Gerami-
Nejad M, Edelson BT, et al. Skin-resident mu-
rine dendritic cell subsets promote distinct and
opposing antigen-specific T helper cell re-
sponses. Immunity 2011;35:260e72.
Lanternier F, Pathan S, Vincent QB, Liu L,
Cypowyj S, Prando C, et al. Deep dermato-
phytosis and inherited CARD9 deficiency.
N Engl J Med 2013;369:1704e14.
Li J, Vinh DC, Casanova JL, Puel A. Inborn errors
of immunity underlying fungal diseases in
otherwise healthy individuals. Curr Opin
Microbiol 2017;40:46e57.
Martinez-Martinez L, Martinez-Saavedra MT,
Fuentes-Prior P, Barnadas M, Rubiales MV,
Noda J, et al. A novel gain-of-function STAT1
mutation resulting in basal phosphorylation of
STAT1 and increased distal IFN-gamma-
mediated responses in chronic mucocutaneous
candidiasis. Mol Immunol 2015;68(2 Pt. C):
597e605.
Nielsen J, Kofod-Olsen E, Spaun E, Larsen CS,
Christiansen M, Mogensen TH. A STAT1-gain-
of-function mutation causing Th17 deficiency
with chronic mucocutaneous candidiasis,
psoriasiform hyperkeratosis and dermatophy-
tosis. BMJ Case Rep 2015.
Sakuragi Y, Sawada Y, Hara Y, Ohmori S,
Omoto D, Haruyama S, et al. Increased circu-
lating Th17 cell in a patient with tinea capitis
caused by Microsporum canis. Allergol Int
2016;65:215e6.
Sparber F, LeibundGut-Landmann S. Interleukin
17-mediated host defense against Candida
albicans. Pathogens 2015;4:606e19.
www.jidonline.org 1693