Journal of Dermatology 2015; 42: 236–244

doi: 10.1111/1346-8138.12718

REVIEW ARTICLE

Immunoresponses in dermatomycoses Carren Sy HAU,1 Yayoi TADA,1 Naoko KANDA,2 Shinichi WATANABE1 1

Department of Dermatology, Teikyo University School of Medicine, and 2Department of Dermatology, Kosei General Hospital, Tokyo, Japan

ABSTRACT Contact with fungal pathogens initiates a series of host responses beginning with innate immunity, which leads to fungal recognition and microbial killing. The innate immune system also modulates the adaptive immune responses, leading to the establishment of immunological memory and protection against pathogens. In the case of dimorphic fungi such as Candida albicans and Malassezia, the immune system plays an important role in tolerance and resistance when managing the organisms either as commensal microbiota or invading pathogens, and disruption of this balance can result in pathological consequences for the host. In addition, Malassezia and dermatophytes have immunomodulatory capabilities that allow them to adapt to their environments and they may exert different effects in healthy and diseased skin. Here, we discuss the host immune responses to dermatomycoses caused by dimorphic fungi such as C. albicans and Malassezia as well as dermatophytes such as Trichophyton spp. and Arthroderma benhamiae to gain a better understanding of the mechanisms of the host– dermatomycosis interaction.

Key words:

Candida, dermatomycoses, dermatophytes, fungus, Malassezia.

INTRODUCTION Fungal infections in the skin, or dermatomycoses, are highly prevalent and may affect 20–25% of the population worldwide. Superficial skin fungal infections comprise the majority of these cases, most commonly caused by dermatophytes, but Candida albicans and Malassezia are also common etiologic agents.1 Contact with fungal pathogens initiates a series of host responses beginning with innate immunity, which is activated by the recognition of highly conserved signature molecules in fungi known as pathogen-associated molecular patterns (PAMP) by pattern-recognition receptors (PRR) found on host immune cells. Microbial killing ensues from phagocytosis and the production of inflammatory and antimicrobial compounds by these cells. The innate immune system also initiates and modulates the adaptive immune responses manifested by the presentation of microbial antigens, leading to the establishment of immunological memory and protection against pathogens.2– 4 In the case of opportunistic fungi, the immune system plays an important role in tolerance and resistance when managing the organisms either as commensal microbiota or invading pathogens, and disruption of the ability to discriminate can result in pathological consequences for the host. Thus, fungal infections may range from acute, limited cutaneous and mucocutaneous manifestations to severe, chronic and life-threatening conditions depending on the immune status of the host and the stability of the epithelial barrier.5

In this article, we will review the host immune responses to superficial skin fungal infections caused by dimorphic fungi such as Candida albicans and Malassezia spp. as well as dermatophytes such Trichophyton spp. to gain a better understanding of the mechanisms of the host–dermatomycosis interaction.

CANDIDA ALBICANS Approximately 200 yeast species make up the genus Candida. Of the organisms that are pathogenic to humans, C. albicans is the most common and medically important representative of the group as it accounts for 70–80% of all candidal infections. C. albicans is a commensal fungus that colonizes the oropharynx in up to 50% of normal individuals and in the vaginal mucosa of 25–30% of asymptomatic and healthy women.6 However, it can also cause recalcitrant diseases such as oral and oropharyngeal candidiasis (OPC), vulvovaginal candidiasis (VVC), mucocutaneous candidiasis (CMC) in individuals with inherited primary immunodeficiency conditions such as hyperimmunoglobulin (Ig)E syndrome (HIES) and autoimmune polyendocrinopathy candidiasis ectodermal dystrophy (APECED). Secondary immunodeficiencies are considered as the most common predisposing factors for C. albicans infection and they may even lead to disseminated candidiasis, for example, diabetes mellitus, HIV–AIDS, neutropenia secondary to cancer chemotherapy, immunosuppression for transplant recipients and patients on chronic corticosteroid therapy.7

Correspondence: Yayoi Tada, M.D., Ph.D., Department of Dermatology, Teikyo University School of Medicine, 2-11-1 Kaga, Itabashi-ku, Tokyo 173-8605, Japan. Email: [email protected] Received 14 October 2014; accepted 16 October 2014.

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Fungal dimorphism – the ability to grow as unicellular, budding yeast cells or filamentous hyphae and pseudohyphae under specific conditions – renders C. albicans pathogenic. PAMP such as mannan and mannoproteins are found in the fungal outer cell wall while the inner cell wall contains b-1,3-glucan (constituting 40% of the cell wall) and chitin, which also constitutes the cell wall. The cell wall proteins from the outer layer are attached to the inner framework via glycosylphosphatidylinositol remnants that are linked to the skeletal polysaccharides through b-1,6-glucan.5–8 Although normally hidden beneath the mannoprotein layer, b-glucan may be exposed on the cell surface in the region of bud scars during hyphal transition.4 Thus, the cell wall of C. albicans is a dynamic therapeutic target with numerous PAMP being recognized by various PRR: Toll-like receptors (TLR) such as TLR2, which binds to phospholipomannan and b-glucan, and induces pro-inflammatory responses against Candida in cooperation with dectin-1.9–11 TLR4 binds to O-linked mannan and induces tumor necrosis factor (TNF)-a production in monocytes and macrophages.12 These responses are channeled through myeloid differentiation factor 88 (MyD88), an important adaptor molecule in the TLR signaling pathway, leading to the activation of nuclear factor-jB (NF-jB), a transcription factor that is responsible for the expression of numerous cytokines and chemokines (Fig. 1).8,13,14 Another relevant set of PRR for fungal PAMP include the Nod-like receptors (NLR) such as NLR family, pyrin domaincontaining (NLRP)1, NLRP3 and NLR family, CARD domaincontaining protein 4 (NLRC4) which, when complexed with several adaptors and proteases, forms the inflammasome that activates caspase 1, leading to the processing of pro-interleukin (IL)-18 and pro-IL-1b into active cytokines such as IL-18, and IL-1b that is upstream of T-helper (Th)1 and Th17 activation in macrophages and other cells.15,16 Deficiencies in NLRP3 in hematopoietic cells and NLRC4 in mucosal stromal cells lead to decreased expressions of IL-17A, IL-17F and IL17 receptor A, thus linking the actions of inflammasomes and IL-17 production.17 The most important set of PRR that recognize C. albicans are the C-type lectin receptors (CLR): dectin-1, dectin-2, macrophage-inducible C-type lectin (mincle), the mannose receptor (MR), dendritic cell-specific ICAM3-grabbing non-integrin (DCSIGN), Langerin, mannose-binding lectin and galectin-3.8,18 Similar to TLR, these receptors mediate signals via NF-jB, and also through mitogen-activated protein kinases (MAPK) which lead to the induction of numerous pro-inflammatory molecules.19,20 We will focus on the first four C-type lectin receptors which play principal roles in immune responses against superficial skin fungal infections (Fig. 1). Dectin-1 is a type II transmembrane receptor with a single extracellular carbohydrate recognition (lectin-like) domain and immunoreceptor tyrosine activation motif (ITAM) in its cytoplasmic tail that is responsible for cell activation.21 It is found on primary mononuclear cells, dendritic cells (DC), macrophages and keratinocytes (KC), and is the predominant receptor for b-glucan. Downstream intracellular signaling triggered by dectin-1 is mediated through the signaling complex spleen tyrosine kinase-protein kinase C d-caspase adaptor recruitment

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Figure 1. Pattern recognition receptors for dermatomycoses. The pathogen-associated molecular patterns of Candida albicans, Malassezia spp. and dermatophytes are recognized chiefly by Toll-like receptors (TLR), dectin-1, mincle, dectin-2 and the mannose receptor (MR) which initiate a cascade of signals that induce the nuclear factor (NF)-jB and mitogenactivated protein kinase (MAPK) pathways, leading to the development of T-helper (Th)17 and Th1 cells which play important roles in the host immune responses against dermatomycoses. FcRc, Fc receptor-c; IL, interleukin. domain-containing protein 9 (Syk-PKCd-CARD9), or the noncanonical serine-threonine kinase Raf-1, which integrates with the Syk pathway at the level of NF-jB.22 PKCd was recently found to be activated by dectin-1 and induces phosphorylation of CARD9. Mice deficient in PKCd or CARD9 are shown to be susceptible to systemic candidiasis.23,24 Other signaling pathways involved in dectin-1-mediated responses are MAPK and nuclear factor of activated T cells.25,26 Recently, it has been reported that aside from NLRP3 and NLRC4, a non-canonical caspase-8 inflammasome is dependent on dectin-1 for activation, resulting in the maturation of pro-IL-1b to IL-1b.27 The ability of dectin-1 to trigger immune responses is dependent on cell types. For example, engagement of dectin-1 on antigen-presenting cells induces various responses including DC maturation, ligand uptake by phagocytosis and endocytosis, the respiratory burst, the production of arachidonic acid metabolites, and the production of cytokines and chemokines such as TNF-a, CXC chemokine ligand (CXCL)2, IL-6, IL-10 and IL-23.26 Dectin-1 also cooperates with TLR such as TLR2, leading to responses such as the respiratory burst and synergistic production of pro-inflammatory cytokines such as TNF-a, IL-6, IL-10 and IL-23, and decreased production of IL-12 in

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macrophages and DC.9,28 The reciprocal regulation of IL-23 and IL-12 may ultimately drive a Th17-skewed adaptive immune response via the development of regulatory T cells (Treg). Blocking of dectin-1 in peripheral blood mononuclear cells (PBMC) led to the suppression of TNF-a, IL-6 and IL-10 production, indicating that dectin-1 is non-redundant and its effects cannot be supplemented by other receptors despite their overlapping roles.28 On the other hand, immune responses induced via stimulation through dectin-1 on KC differ from those through antigen-presenting cells. We have shown that normal human epidermal KC express dectin-1 and respond to b-glucan stimulation by producing IL-8, IL-6 and IL1a which are upregulated by a high calcium concentration and the addition of the danger signal adenosine 50 triphosphate and polyinosinic:polycytidylic acid, a TLR3 ligand, via the extracellular signal-regulated kinase 1/2 and p38 MAPK signaling pathways.29 Several reports suggested that dectin-1 and its signaling pathway are dispensable for immune defense against Candida infection. Host mutations in dectin-1 or CARD9 are linked to susceptibility to developing Candida infections. In a family with members who were homozygous for a dectin-1 mutation manifesting with recurrent VVC or onychomycosis, it was found that defective surface expression of dectin-1 due to Tyr238X polymorphism results in lack of b-glucan recognition, and monocytes and macrophages had defective IL-6 and reduced IL-17 production after b-glucan stimulation although killing of C. albicans by neutrophils was normal.30 Glocker et al.31 reported the same phenotype in a family with a mutation to CARD9, although CARD9-deficient patients generally present with a more severe phenotype than patients with dectin-1 deficiencies as they are susceptible to invasive candidiasis.32 Dectin-2 is found at high levels in DC and can be inducibly expressed in macrophages after activation. It is shown to recognize a-mannan and to preferentially bind the hyphal forms of C. albicans, Microsporum audouinii and Trichophyton rubrum.33,34 After the recognition of hyphae, dectin-2 couples with the Fc receptor-c (FcRc) chain, an ITAM-containing adaptor, leading to the upregulated secretion of TNF-a and IL-1 receptor antagonist.34 It also exerts important Th17-inducing activities including the recruitment and activation of neutrophils and defensins in response to C. albicans. Saijo et al. reported that mice deficient in dectin-2 were susceptible to Candida infection, and that fungal a-mannan did not induce any cytokine production from dectin-2 deficient DC. They also found that both the yeast and hyphal forms of C. albicans can induce the secretion of IL-6, IL-1b and IL-23 – cytokines which are crucial for Th17 differentiation – in a dectin-2-dependent manner in bone marrow-derived DC, with a higher cytokine inducing activity noted in hyphae which is consistent with the finding that dectin-2 preferentially binds to these structures.35 Based on their results, they noted that dectin-2 rather than dectin-1 was mainly involved in Th17 differentiation, possibly because dectin-1 is located within the inner cell wall and is only exposed on the bud scars of the fungus as it changes from yeast to hyphae.4,35 Mincle also couples with the FcRc chain upon recognizing a-mannans.36 It is expressed predominantly on macrophages

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and, together with TLR2, it has been shown to have a role in the induction of TNF-a production in these cells upon exposure to Candida yeasts.37 Together with dectin-1 and dectin-2, mincle couples downstream directly or indirectly to Syk-CARD9, ultimately promoting Th17-skewed responses. On the other hand, MR recognizes N-linked mannans from C. albicans and engages macrophages and DC for microbial killing. In conjunction with TLR2/dectin-1 signaling, MR can also induce IL-17 production in response to Candida cell wall mannan moieties.10,38,39 As illustrated in Figure 2, aside from providing a primary protective effect against Candida, the innate immune cells engaged by PRR also instruct the adaptive arm of the immune responses through the production of pro-inflammatory cytokines/chemokines, co-stimulatory signals and antigen uptake and presentation (Fig. 2).40 Protective adaptive responses against Candida are mediated mainly by CD4+ Th cells. Before the discovery and characterization of Th17 cells, immune defense against C. albicans was regarded as Th1-dominant

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Figure 2. Immune responses to Candida albicans. Fungal recognition by pattern-recognition receptors (PRR) triggers a series of immune responses against C. albicans. Antigenpresenting cells such as Langerhans cells (LC) in the epidermis migrate to the lymph nodes to induce na€ıve T cells to differentiate into T-helper (Th)1 and Th17 cells. Other antigen-presenting cells such as macrophages are also activated and produce interleukin (IL)-1b, IL-6 and IL-23, leading to Th17 differentiation via the transcription factors signal transducer and activator of transcription (STAT)3 and RAR-related orphan receptor (ROR)ct. Th17 cells produce IL-17A/F, cytokines which attract neutrophils, and IL-22 which induces keratinocytes to produce antimicrobial peptides (AMP) such as defensins and S100 proteins. In addition, Th1 cells produce interferon (IFN)-c, which activate macrophages. DC, dendritic cell; IFN, interferon; LC, Langerhans cells.

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response involving cells producing interferon (IFN)-c, with Th2 responses leading to increased susceptibility to C. albicans infection in IFN-c receptor-deficient mice.41–45 However, the findings in OPC mouse models showed inconsistencies in the theory, as IL-12p40/ and not IFN-c/ mice were susceptible to Candida, indicating that the immune responses may rely more on Th17 cells that produce IL-17A, a population distinct from Th1/Th2 cells. IL-23, a dimeric cytokine composed of IL12p40 and IL-23p19, plays an important role in the maintenance, expansion and downstream effector functions of Th17 cells, which explains the important findings of Candida susceptibility in IL-12p40/ mice which were at first attributed to Th1.46–49 Currently, it is found that the Th17 subset plays a central role in resistance to OPC and CMC, and mice deficient in IL-17RA and IL-17RC are susceptible to Candida infections.50 At the oral mucosa, host defense induced by IL-17 may be mediated by the secretion of antimicrobial peptides (AMP) and neutrophil recruitment via chemokines and granulopoietic cytokines.48,51 As for defense against cutaneous candidiasis, it is known that Th17 cells and cytokines serve as a link between the epithelial and adaptive host defenses. IL23, IL-6 and IL-1b produced by PRR recognition of Candida PAMP in innate immune cells induce Th17 cell differentiation via the transcription factors RAR-related orphan receptor (ROR)ct and signal transducer and activator of transcription (STAT)3, which plays a critical role in the expansion and function of Th17 cells.16 In a vaginal candidiasis model, blocking of Th17 differentiation by the compound halofuginone resulted in significant reduction of IL-17 production and a corresponding increase in fungal burden.52 After differentiation, Th17 cells produce IL-17A/F and IL-22 which induce epithelial and stromal cells to produce pro-inflammatory cytokines, granulocyte colony-stimulating factor and neutrophil-attracting chemokines such as CXCL1, CXCL5 and IL-8, and AMP such as b-defensins, cathelicidins and S100 proteins which can directly kill fungi and other pathogens.16,53 Eyerich et al. found that IL-22 enhances the TNF-a-induced regulation of multiple innate defense genes such as AMP S100A7 and human-b-defensin 2 (HBD-2) and chemokines such as CXCL9/10/11 in human KC in vitro. In accordance with this, KC stimulated with Th22 supernatants or recombinant IL-22 and TNF-a inhibited the growth of C. albicans and maintained the survival of KC.54 On the other hand, Kagami et al. reported that mice deficient in IL-23 or IL-17A demonstrated delayed healing and decreased IL-17A production after skin infection with C. albicans compared with wild-type mice or mice deficient in IL-12 or IL-22, demonstrating that IL-23 and IL-17A, but not IL-12 or IL-22, are required for optimal host defense against chronic cutaneous candidiasis.55 Their findings indicate that IL-17 and IL-23 are principally involved in immune defense against skin and mucosal Candida infections. Skin-resident DC also play an important role against C. albirta  et al.56 showed that among the subsets of skin cans. Igya DC, direct antigen presentation by Langerhans cells was sufficient and crucial in the generation of antigen-specific Th17 cells in a C. albicans skin infection murine model.

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Along with murine models for cutaneous and mucosal candidiasis, human primary immunodeficiency disorders such as HIES and APECED, which present with CMC, highlight the importance of Th17 cells in host defense against C. albicans.32 Protection against mucocutaneous candidiasis relies mainly on cell-mediated immunity, particularly on T cells.57 Individuals with HIES have dominant negative mutations in stat3 which is important for signaling downstream of IL-6 and IL-23 as well as the expression of IL-17, leading to defective Th17 development and function. Thus, patients have significantly lower CD4+/IL-17+ Tcell counts compared with normal subjects.47,58–60 Furthermore, DC of HIES patients had defective IL-10 signaling, leading to the impairment of suppression of cytokine production and T cell proliferation. The generation of Foxp3+-induced Treg cells educated by IL-10-treated DC was also impaired, disrupting the balance of Th2 and Treg cells. As a result, patients present with extremely high IgE levels, atopic dermatitis-like skin lesions and recurrent superficial bacterial infections (cold abscesses) as well as fungal infections such as CMC.61 APECED is a rare, severe autoimmune syndrome arising from mutations in the autoimmune regulator (AIRE), resulting in aberrant thymic self-tolerance mechanisms and multi-organ autoimmune disease. Susceptibility to Candida infections are due to high levels of neutralizing autoantibodies to Th17 cytokines such as IL-17A, IL-17F and IL22.62 Taken together, these findings highlight the importance of the various steps of the host immune responses against Candida albicans, from pathogen recognition to the initiation of innate immunity and the shaping of the adaptive immune responses. The recruitment of neutrophils and AMP production induced by Th17 cells play a central role in defense against C. albicans, and various ongoing studies continue to shed light on the complex interplay between innate and adaptive immune antifungal responses and other immune cells which may emerge as key players in the defense against Candida infections. The Th17 pathway is also central to the pathogenesis of other diseases such as arthritis and psoriasis, and biologic drugs aimed at manipulating Th17 components are now under development. However, the use of these new classes of drugs also raises the possibility of opportunistic fungal infections becoming more frequent, and Candida infections such as CMC resulting as a possible adverse effect associated with the clinical use of antiIL-17 therapies must be taken into careful consideration.16

MALASSEZIA Like Candida, Malassezia is a dimorphic fungus, generally tolerated by the immune system as part of the skin microflora under normal conditions, but it may become pathogenic when skin homeostasis is disrupted. The interaction of Malassezia yeasts with the skin is multifaceted. Depending on the species, Malassezia can up- or downregulate the immune responses as evidenced by the range of Malassezia-associated clinical conditions that involve little to significant inflammation. Nine species of Malassezia have been isolated in human skin, the most common being Malassezia globosa, Malassezia restricta, Malassezia dermatis, Malassezia sympodialis and Malassezia furfur.63,64

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Toll-like receptors have long been considered as PRR involved in the recognition of Malassezia.65,66 The CLR mincle is also shown to be an activating receptor for Malassezia. Malassezia pachydermatis induces macrophages to produce TNF-a, CXCL2 and IL-10; these responses were significantly impaired in mincle/ macrophages.67 Recently, it has been reported that Malassezia is cooperatively recognized by mincle and dectin-2, which can identify lipophilic and hydrophilic components in the fungus, respectively.68,69 It was shown that ligands for mincle included glyceroglycolipid and unique mannosyl fatty acids linked to mannitol, while an O-linked mannobiose glycoprotein was identified as a dectin-2 ligand. Both CLR are coupled with the FcRc chain, leading to the production of TNFa and IL-10 in DC upon exposure to M. furfur. These responses were abrogated in mincle/ and dectin-2/ DC. Th17 responses were not detected although it is possible with one of the mincle ligands.68 The cell wall matrix of Malassezia also contains b-glucan.69 In studying the interaction of mast cells (MC) with M. sympodialis, Ribbing et al.70 reported that progenitor-derived MCs from healthy controls and atopic dermatitis (AD) patients responded to M. sympodialis by upregulating mincle mRNA expression. Furthermore, compared with control subjects, the MC from AD patients contained more intrinsic granule mediators such as histamine, exhibited enhanced IL-6 release upon exposure to M. sympodialis, and had an impaired upregulation of dectin-1, which recognizes b-glucan. In addition, analysis of skin sections from healthy control and AD patients revealed MC as the predominant dectin-1-expressing cell type in the skin.70 These findings suggest that dectin-1mediated immune responses in MC against Malassezia are highly probable and further investigation is warranted. There are mixed reports on the capacity of Malassezia to induce inflammatory responses in KC. The absence of inflammation in the lesions of pityriasis versicolor (PV) despite the heavy fungal load has been attributed to the downregulating effect of M. furfur.71 Furthermore, Vlachos et al.66 reported that Malassezia-derived indoles such as indolo[3,2-b]carbazole and malassezin can modulate DC function by downregulating the ability of DC to mature and present antigens in response to TLR stimulation. Indeed, we found that M. furfur did not induce significant cytokine secretion in human KC per se, although it induced IL-4 production in PBMC from AD patients and IFN-c production in patients with PV. It did not induce either IL-4 or IFN-c production in the PBMC of normal subjects.72,73 On the other hand, Baroni et al. reported that in the HaCat KC cell line, M. furfur downregulated IL-1a production and upregulated IL-10 and transforming growth factor (TGF)-b which led to the inhibition of IL-6 and TNF-a production.74 Baroni et al.65 also reported that human adult KC infected with M. furfur, along with M. furfur-positive psoriatic skin biopsies, showed an upregulation for HBD-2, HBD-3 and IL-8 mRNA expression, and that HBD2 and IL-8 gene expressions were dependent on TLR2 and MyD88. The discrepancy in these findings may be explained by highly variable results that may be obtained with different KC cultures and cell lines as well as different Malassezia strains and the conditions of the specimens (such as the presence or absence of the lipid layer) which were used in the experiments.64,75

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Seborrheic dermatitis (SD) is a recurrent inflammatory condition characterized by erythematous papules or plaques with greasy flakes on the scalp, face and upper trunk. We have reported that M. pachydermatis, Malassezia slooffiae and M. sympodialis yeasts can induce the secretion of IL-1b, IL-6, IL-8 and TNF-a in human KC.72 MCP-1, a potent chemoattractant for monocytes, was not induced by these yeasts, and these results correlate with the histopathological features of Malassezia SD: superficial perivascular and interstitial lymphocytic infiltrates accompanied by some neutrophils in the dermis and focal exocytosis of lymphocytes and occasional pyknotic neutrophils within parakeratotic foci in the epidermis, but monocyte infiltration is not observed.72 Recently, we reported that an M. restricta extract increased the mRNA and protein expression of Th1-attracting CXCL-10 and STAT1 activity and phosphorylation in KC.76 Interestingly, it is hypothesized that Malassezia-induced CXCL10 expression is involved in the development of AD in the seborrheic region but not in the typical intertriginous AD region. Furthermore, we noted that various antimycotics suppressed M. restrictainduced CXCL10 mRNA and protein expression as well as STAT1 activity and phosphorylation, the latter process due to an increase in 15d-Prostaglandin J2 production in KC induced by the antimycotic agents. The Malassezia extract did not induce CCL22/17, indicating that it may not act as an AD triggering factor to prime the Th2 responses. Rather, it may switch the responses from Th2 to Th1 and sustain or exacerbate the chronic inflammation in AD.73,76 Based on existing data, Malassezia exerts multifaceted effects on the cutaneous immune system (Fig. 3).

DERMATOPHYTES Dermatophytoses, or tinea infections, are the most common superficial fungal infections in humans. They are caused by dermatophytes which may be classified as anthropophilic (T. rubrum, Trichophyton tonsurans), zoophilic (Trichophyton mentagrophytes, Arthroderma benhamiae) or geophilic (Microsporum gypseum).77,78 In contrast to Candida and Malassezia, dermatophytes are not opportunists but are obligate pathogens that require keratin found in the skin stratum corneum, hair and nails for their survival. Thus, the ability to degrade keratin is a dermatophyte virulence factor. Dermatophytes produce several proteases such as subtilins and fungalysins and A. benhamiae has been shown to exhibit different protease gene expression profiles in vitro and in vivo, which suggests that these enzymes may perform roles other than keratin degradation. Furthermore, the gene encoding the serine protease subtilisin 6, a major allergen in T. rubrum (also called Tri r2) and putatively linked to host inflammation, was found to be strongly upregulated during A. benhamiae infection.79–81 Further studies are underway to determine the role of these proteases in dermatophyte pathogenicity and it would be interesting to determine if they possess immunomodulatory capabilities. Dermatophyte recognition is carried out by PRR such as TLR2 and TLR4 as well as dectin-1, which are reported to mediate responses to T. rubrum conidia in HaCat KC by

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Malasseziaspp

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Figure 3. Immunomodulatory effects of Malassezia spp. on keratinocytes. Although they can downregulate immune responses, Malassezia spp. are also reported to induce the production of various cytokines and defensins such as interleukin (IL)-8, IL-6, IL-1b, human-b-defensin 2 (HBD)-2, HBD-3, tumor necrosis factor (TNF)-a and CXC chemokine ligand (CXCL)-10 in keratinocytes. Macrophages and dendritic cells (DC) are activated and produce TNF-a, CXCL2 and IL-10. The T cells involved are predominantly T-helper (Th)1 cells producing IFN-c, which lead to further macrophage activation. LC, Langerhans cells.

T. tonsurans and A. benhamiae, Shiraki et al.88 reported that T. tonsurans-infected KC secreted only eotaxin-2, IL-8 and IL16, whereas A. benhamiae induced the production of a broad variety of pro-inflammatory and immunomodulatory cytokines/ chemokines. Complementary DNA microarray analysis showed that A. benhamiae upregulated the genes encoding IL-1b, IL-2, IL-4, IL-6, IL-10, IL-13, IL-15, IL-16, IL-17 and IFN-c, while T. tonsurans only upregulated genes encoding for IL-1b and IL6. Both dermatophytes enhanced IL-8 mRNA expression in KC.88 In mice infected with A. benhamiae and Arthroderma vanbreuseghemii, Cambier et al.89 found that the dermal inflammatory infiltrate of lesional skin contained numerous PMN, macrophages and DC. Both dermatophytes induced significantly increased mRNA expressions of TGF-b, IL-1b and IL6, and A. benhamiae was shown to induce elevated IL-22 mRNA expression as well. These findings indicate that the cutaneous acquired immune responses to dermatophyte infections involve Th1, Th2 and Th17 components, and this is in line with other studies involving Trichophyton spp. (Fig. 4).89 It has been reported that Trichophyton-induced inflammation involves the proliferation of PBMC and IFN-c production.90,91 IFN-c gene expression and IFN-c-positive CD4+ cells were Dermatophytes

IL-4, IL-5 IL-13

IL-8, IL-6, IL-2, IL-15, IL-1β, IL-10, IL-16, TGF-β, eotaxin 2

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upregulation of IL-8, IFN-c, IL-6 and IL-13.82 Nakamura et al.83 also found that dectin-1 neutralizing antibody inhibited the promotion of IFN-c production in C57BL/6 mice challenged with Trichophyton, indicating that dectin-1 expressing immune cells have important roles in Trichophyton-induced IFN-c production. In addition, Chung et al. reported that DC-HIL, a highly glycosylated type I transmembrane protein that is constitutively expressed at high levels in DC and macrophages, serves as a PRR for dermatophytic fungi by binding to T. rubrum and M. audouinii but not C. albicans. Upon binding to dermatophytes, it was found that DC-HIL potentiates the antigen-presenting capacity of DC while also negatively regulating T-cell activation.84 On the other hand, Trichophyton schoenleinii, the causative agent of trichophytosis and tinea favosa of the scalp, is shown to induce the production of IL-1b in THP-1 cells, a human monocytic cell line, through activation of the inflammasome via NLRP3.85 Infections caused by anthropophilic dermatophytes are generally chronic and accompanied by minimal to varying inflammation.86 On the other hand, infections with zoophilic fungal species such as A. benhamiae, a teleomorph of T. mentagrophytes, can induce more severe inflammation in the human host.87 In a study comparing the cytokine secretion profiles of

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Figure 4. Immune responses to dermatophytes. Anthropophilic dermatophytes such as Trichophyton rubrum, Trichophyton schoenleinii and Trichophyton tonsurans induce the production of interleukin (IL)-8, IL-6, IL-1b and eotaxin-2 in keratinocytes, peripheral blood mononuclear cells (PBMC) and THP-1 cells, macrophages and dendritic cells (DC), while zoophilic dermatophytes such as Arthroderma benhamiae induce a wide range of cytokines including IL-1b, IL-6, IL-8, IL-10, IL-2, IL-15, IL-16, transforming growth factor (TGF)-b, interferon (IFN)-c (T-helper [Th]1), IL-17 (Th17), IL-4, IL-5 and IL-13 (Th2), leading to various pro-inflammatory processes such as neutrophil chemoattraction as well as macrophage and DC activation resulting in fungal killing and clearance.

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found to be enhanced in tinea lesions, indicating that Trichophyton-induced dermatophytosis is a Th1-type contact hypersensitivity.92 However, additional studies also showed that in AD and patients with immunodeficiencies, Trichophyton infection can induce Th2-dominant reactions with high levels of IL-4, IL-5 and IgE.93,94 The application of trichophytin, a Tricophyton antigen extracted from the filtrate of T. mentagrophytes culture fluid, on Th1-dominant strain C57BL/6 mice, enhanced IFN-c and IL-17A gene expressions in regional lymph nodes and IL-1b, IFN-c, IL-6 and IL-23 in the inflamed auricular skin of C57BL/6 mice, signifying that Th1 cells as well as Th17 cells were induced by Trichophyton antigen. Trichophytin challenge in Th2-dominant strain BALB/c mice resulted in the enhanced expressions of IL-4 in lymph nodes, and thymic stromal lymphopoietin and IL-4 in auricular skin.83 These findings indicate that inflammatory mediators differentially regulate Trichophyton-induced contact hypersensitivity depending on the status of host immunity, signifying that varying acquired immune responses may be noted in patients with different immunological statuses. In conclusion, the interaction between pathogenic fungi and the immune system is highly complex and involves an entire range of responses. Furthermore, certain fungi have adaptive mechanisms and have immunomodulatory capabilities that enable them to survive on the skin. Lessons drawn from understanding the mechanisms that underlie the cutaneous immune responses to superficial skin fungal infections may shed light on future strategies in antifungal treatment.

CONFLICT OF INTEREST:

None.

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