|Year : 2021 | Volume
| Issue : 3 | Page : 389-399
Immunopathogenesis of dermatophytoses and factors leading to recalcitrant infections
Kabir Sardana, Aastha Gupta, Sinu Rose Mathachan
Department of Dermatology, Post Graduate Institute of Medical Education and Research Dr. Ram Manohar Lohia Hospital, New Delhi, India
|Date of Submission||31-Jul-2020|
|Date of Decision||27-Oct-2020|
|Date of Acceptance||20-Dec-2020|
|Date of Web Publication||12-May-2021|
Department of Dermatology, Post Graduate Institute of Medical Sciences, Dr Ram Manohar Lohia Hospital, Baba Kharak Singh Road, New Delhi - 110 001
Source of Support: None, Conflict of Interest: None
| Abstract|| |
The pathogenesis of dermatophytic infections involves the interplay of three major factors: the dermatophyte, the inherent host defense, and the adaptive host immune response. The fungal virulence factors determine the adhesion and invasion of the skin while the immune response depends on an interaction of the pathogen-associated molecular patterns (PAMPs) and damage-associated molecular patterns (DAMP) with pattern recognition receptors (PRRs) of the host, which lead to a differential Th (T helper) 1, Th2, Th17, and Treg response. While anthropophilic dermatophytes Trichophyton rubrum and now increasingly by T. interdigitale subvert the immune response via mannans, zoophilic species are eliminated due to a brisk immune response. Notably, delayed-type hypersensitivity (Th1) response of T lymphocytes causes the elimination of fungal infection, while chronic disease caused by anthropophilic species corresponds to toll-like receptor 2 mediated IL (interleukin)-10 release and generation of T-regulatory cells with immunosuppressive potential. Major steps that determine the ultimate clinical course and chronicity include genetic susceptibility factors, impaired epidermal and immunological barriers, variations in the composition of sebum and sweat, carbon dioxide tension, skin pH, and topical steroid abuse. It is important to understand these multifarious aspects to surmount the problem of recalcitrant dermatophytosis when the disorder fails conventional therapeutic agents.
Keywords: Anthropophilic species, epidermal barrier, fungal virulence factors, immune responses, recalcitrant dermatophytosis, skin pH, steroid abuse, Th1 and Th 17 cells
|How to cite this article:|
Sardana K, Gupta A, Mathachan SR. Immunopathogenesis of dermatophytoses and factors leading to recalcitrant infections. Indian Dermatol Online J 2021;12:389-99
|How to cite this URL:|
Sardana K, Gupta A, Mathachan SR. Immunopathogenesis of dermatophytoses and factors leading to recalcitrant infections. Indian Dermatol Online J [serial online] 2021 [cited 2022 Jan 20];12:389-99. Available from: https://www.idoj.in/text.asp?2021/12/3/389/315874
| Introduction|| |
The pathogenesis of dermatophytic infections involves three major factors, and it is important to understand the interplay between them, in the era of recalcitrant dermatophyte infections., These factors include the fungi, the inherent host factors including the skin barrier function, and the immune response mounted against the fungus. Among these, the type of fungi and immune response of the host play a major role, and these are crucial in causing recalcitrance and relapses. Dermatophytes belong to 3 genera -Trichophyton, Epidermophyton, and Microsporum. These are divided into anthropophilic, zoophilic, and geophilic according to their primary habitat. While possibly in other parts of the world, anthropophilic dermatophyte Trichophyton rubrum is a common cause, but this is now being increasingly replaced by T. interdigitale in some geographical locations.,, T. interdigitale is currently the prevalent strain in India and causes mild inflammation and chronic infections. There are known variations in the fungal virulence factors among different species, and it is likely to be playing a role in the current scenario the country is facing. For example, protease and lipase enzymes vary significantly between T. tonsurans and Trichophyton equinum. This has been reinforced by a study where comparative proteomic analysis of T. rubrum and Trichophyton violaceum revealed differences in the amount and specificity of secreted proteins between them.
Experimental models are required to transcend speciation and to assess the virulence factors and the immuno-pathogenetic pathways of diverse dermatophytes species. The immune responses elicited by zoophilic dermatophytes are studied using guinea pigs and mice. In contrast, in anthropophilic species, studies have been performed in ex-vivo models using epidermal tissues and keratinocyte co-cultures, which could have direct applicability to clinical situations. In spite of this methodological issue of translation of research, we have attempted in this review to distill the vast amount of data to help understand the complex pathogenesis.
Dermatophyte specific factors
The immune response stimulated by Dermatophytes vary depending on the species stimulate an immune response. Trichophyton rubrum causes chronic infections, possibly by the release of glycopeptides that can inhibit the proliferation of T lymphocytes in vitro, thereby suppressing host immunity.
The dermatophytes' armamentaria mainly comprises of the surface molecules for adhesion, secreted enzymes to degrade and metabolise host molecules for nutrition, thermo-tolerance, and dimorphism (i.e., converting between mycelial and conidial forms depending on ambient conditions). It is important to emphasize that though certain factors related to the potential host predispose to dermatophytoses, it is the dermatophyte virulence factors which are primarily implicated for causing infection, regardless of the patient's immune status.
The major steps involved in the establishment and perpetuation of dermatophyte infection are detailed below:
The initial step is the interaction of dermatophytes with the host tissues, and adhesion to the epidermis occurs within 1hour. Adhesins present on the cell wall of fungi are crucial to the initial attachment. The molecules implicated include Sub3 secreted protease of the subtilisin family in M.canis, and sowgp gene and dipeptidyl-peptidase IV (DppIV) of the Trichophyton spp., This is followed by germination, where arthroconidia germinate, and the hyphae quickly enter the stratum corneum to prevent elimination with cell shedding, which occurs within 3-4 hours. Between 24 hours and 3 days, the hyphae spread through the skin. Fibril like structures have been demonstrated in the case of Trichophyton mentagrophytes, facilitating adhesion and thereby preventing elimination from the host tissue. The arthrocidium becomes flat, and the fibril-like structures become short and fine when it invades the deeper layers of the epidermis, leading to increased contact surface with the host tissue and thereby better adhesion and more nutrient acquisition.
On the 4th day, the hyphae reach the granular layer, which coincides with a loss of the integrity of the epidermal barrier. Consequently, the keratinocytes release antimicrobial peptides (AMP) and pro-inflammatory cytokines, resulting in control and, ultimately, the resolution of infection via the immune system's stimulation. Further, there may be a role of biofilm formation by making connections between adjacent arthroconidia.
Enzymatic activity and virulence factors
A critical virulence factor of dermatophytes is best distinguished by its enzymatic activity. Dermatophytes produce several enzymes, including proteases, lipases, elastases, collagenases, phosphatases, and esterases, which have been implicated in host invasion and assimilation of nutrition. The proteolytic enzymes, notably the keratinolytic proteases (keratinases), have a well-established role in the pathogenicity of dermatophytoses helping in invasion into tissues as well as providing oligopeptides and amino acids on keratin breakdown, which are important nutrients for the fungi. It was found that the Trichophyton spp. had the highest keratinase activity in a study that compared the keratolytic action of T. rubrum, T. interdigitale, M. canis, and M. gypseum using spectrophotometry. This high keratinase activity of Trichophyton spp. has been implicated for adaptation of these dermatophytes to human skin and is referred to as “anthropization.”
Lipids are also degraded and utilized by the dermatophytes using relevant enzymes. Probably because of the destructive effects and the resulting alteration in epidermal differentiation by dermatophytes, the epidermal barrier of the glabrous skin is distinctly impaired in tinea. However, in nails, before the action of the keratinolytic proteases can commence, the abundant disulphide bonds present within the hard keratin must be broken. This is achieved by a sulfite efflux pump, encoded by TruSsu1 gene in T .rubrum. Cysteine dioxygenase (CDO) activity is also essential for the same, and hence arthroderma benhamiae cdo1 and ssu1 knockout mutants were found unable to grow on hair and nails.
The role of ambient pH
The initial environment encountered by the dermatophytes on skin and nail is acidic. The acidic pH is maintained by a complex balance between acidifying (products from glands and their breakdown by resident flora, filaggrin–histidine–urocanic acid pathway-related breakdown products) and alkalinizing (ammonia, carbon-dioxide, and bicarbonates) factors.
Proteases that function optimally at an acidic pH are unsuppressed, and keratin utilization begins. The use of keratin as the source of carbon generates metabolites which shift the ambient pH to alkaline. This is associated with the upregulation of proteases with optimal function at an alkaline pH. Thus, the fungus can obtain nutrition from proteins over a wide pH range.
This adaptive pH regulatory mechanism is an important virulence factor and depends on the PacC/Pal signal transduction pathway, which is highly conserved on pathogenic fungi, including dermatophytes. PacC is a transcriptional regulator regulating the pH-dependent gene expression. The proteolytic cleavage of PacC is triggered by the signaling cascade which is composed of the six pal genes (palA, palB, palC, palF, palH, and palI) that senses the alkaline pH.,,,,, While the initiation of dermatophytic infection is promoted by the genes upregulated at acidic pH, those that function at alkaline pH are crucial for its maintenance. Also, the growth in keratin cultures containing hsp90 inhibitor lowered the pacC transcripts concentration, indicating an association between pacC and hsp90 that may affect fungal virulence.
The role of heat shock proteins (HSP)
Various HSPs have been found to be over-expressed during dermatophyte invasion of host tissues. T. rubrum grown on human nails in vitro resulted in an increased expression of hsp60, hsp70, and hsp78 genes, while hsp70, hsp90, hsp related gene hsf1 and hspSSc1 are overexpressed when it is grown on skin. Fungal virulence on the human nail was diminished when 17-allylamino-17-demethoxygeldanamycin (17-AAG, Hsp90 inhibiter) was used in an inhibitor concentration-dependent manner, suggesting the involvement of this HSP in pathogenicity. Chemical inhibition of hsp 90 results in increased susceptibility of T. rubrum to itraconazole and micafungin, which can be used clinically as this is suggestive of a potential for combination therapy with existing antifungals.
Toxin production has also been implicated, and the salient compounds are xanthomegnin released by T. megninii, T. rubrum, and T. violaceum, hemolysins released by T. rubrum and T. interdigitale and , lipophilic toxins, such as xanthomegnin and aflatoxin-like substances all of which are known to have immunosuppressive effects.
Role of mannan
Mannan, a glycoprotein component of the fungal cell wall, facilitates infection by inhibiting the proliferation of keratinocytes, thus preventing shedding, and suppression of the inflammatory response. T.rubrum produces mannan in larger amounts than M.canis. Furthermore, mannan produced by T.rubrum inhibits cell proliferation and lympho-proliferation more effectively.
Although many dermatophyte strains have been shown to form biofilms under experimental conditions and on ex-vivo nail tissue, their existence on the skin in tinea corporis/cruris has not yet been demonstrated.
| Host Immune Response to Dermatophytes|| |
There are several host defense mechanisms that prevent the establishment of tinea infections, including the physical and chemical composition of skin, UV light exposure, lack of humidity and temperature, action of phagocytic cells, and commensal microbiota. The rapid proliferation of keratinocytes also plays an important role in defense against dermatophyte infections by continual renewal and epithelial shedding. While there is a suggestion that commensal skin fungi may play a role in host-dependent immunity and the various fungi isolated including Malassezia, Penicillium and Aspergillus amongst others (Alternaria, Candida, Rhodotorula, Cladosporium and Mucor) — their interaction with dermatophyte is as yet unknown though they may influence the Th17 cell and its pathway. The various host defense mechanisms are listed in [Table 1].
|Table 1: Summary of the various host defense mechanisms against Dermatophyte Infection|
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Dermatophyte- keratinocyte immune interaction
Keratinocytes are the first cellular elements that come into contact with dermatophytes during infection and are capable of modulating the host immune response. Upon exposure to dermatophytes or their antigenic determinants, the keratinocytes produce a wide range of cytokines, including interleukin (IL)-8 (a potent neutrophil chemotactic factor), the pro-inflammatory cytokine TNF (tumor necrosis factor)-α, IFN (interferon)- γ, IL-1ß, IL-22 and IL-16 among others, to destroy dermatophytes [Figure 1].
|Figure 1: A depiction of the immune responses to dermatophyte infection. While Th1 and Th17 response leads to clearance of the dermatophytes, Th2 response inhibits fungal clearance and persistent Treg activation leads to chronic persistent infections. The immune response elicited also varies with the dermatophyte species involved. While zoophilic dermatophytes such as Arthroderma benhamiae induce a wide range of cytokines, anthropophilic dermatophytes such as Trichophyton rubrum induce the production of a limited array of mediators (highlighted in bold)|
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The ability to prompt the secretion of pro-inflammatory cytokines in the keratinocytes varies among the dermatophytes species. Zoophilic species like Arthroderma benhamiae, can lead to the expression of various cytokines by the keratinocytes, which lead to enhanced inflammation. On the contrary, T. tonsurans, an anthropophilic dermatophyte, has a limited ability to induce cytokines, thus leading to less inflammation.,
A study comparing the cytokine profile of T. tonsurans and A. benhamiae found that T. tonsurans triggered eotaxin-2, IL-16, and IL-8 secretion from the infected keratinocytes, whereas A. benhamiae produced a wide variety of pro-inflammatory and immunomodulatory cytokines/chemokines. Complementary DNA microarray analysis shows that the genes encoding IL-1ß, IL-2, IL-4, IL-6, IL-10, IL-13, IL-15, IL-16, IL-17, and IFN- γ were upregulated by A. benhamiae, while T. tonsurans only upregulated genes encoding for IL-1ß and IL-6. Also, both dermatophytes enhanced the IL-8 mRNA expression in keratinocytes. It was also found that T. mentagrophytes induces higher expression of IL-1α by keratinocytes than T.rubrum. Another recent study conducted to distinguish the change in the gene expression of HaCaT (Cultured human keratinocyte) cell line following dermatophytic infection found that pro-inflammatory cytokines and chemokines triggered the infiltration of neutrophils and other immune cell to the infection site following zoophilic M gypseum infection due to the upregulated expression of genes related to immune response, while with T rubrum, metabolic pathway genes were upregulated instead immune response-related genes. This corroborates with the clinical observations that in acute infections provoked by the zoophilic fungi T. mentagrophytes and M. gypseum, marked neutrophils are seen in the epidermis, whereas T. rubrum lead to chronic infections and are characterized by a mononuclear infiltrate. 11 Trichophyton-induced inflammation causes the proliferation of peripheral blood mononuclear cells (PBMC) and the production of IFN- γ and IFN- γ -positive CD4+ cells leading to a Th1 response, [Figure 1].
In addition to the vigorous immune response, antimicrobial peptides (AMP) such as cathelicidins and defensins are secreted by the human keratinocytes with likely antifungal activity as well. In vitro fungistatic and fungicidal activity of human-defensins and cathelicidin (LL-37), respectively against T. rubrum, has been shown by several authors, and also there is increased expression of AMP in vivo in tinea corporis caused by this trichophyte.,
Innate immune response
Epidermal dendritic cells (DC), especially Langerhans cells (LC), are crucial in initiating and modulating the adaptive immune responses against dermatophytes. A recent study has shown that a reduced number of LC in the epidermis increases the risk of dermatophyte infections. These cells contain receptors for pathogen-associated molecular patterns (PAMPs) called pattern recognition receptors (PRRs), such as, Toll-like receptors (TLRs), C-type lectin receptors (CLRs), and the galectin family proteins, that sense the PAMPs and the damage-associated molecular patterns (DAMPs) that are present on fungi. [Figure 2] The major PAMPs for dermatophytes are the cell wall components, mainly glucans and mannans. Apart from TLRs, CLRs form the major receptors involved in recognition of the PAMPs of dermatophytes. These include Dectin-1, Dectin-2, Dectin-3, MR, Mincle, and dendritic cell-specific intercellular adhesion molecule-3 (ICAM-3)-grabbing non-integrin (DC-SIGN) [Figure 2].
|Figure 2: A depiction of the interaction of the pathogen-associated molecular patterns (PAMPS) and the pattern recognition receptors (PRR) for dermatophytes. The major PRRs for dermatophytes included the Toll-like receptors (TLR), dectin-1, minicle and dectin-2 which recognize the mannans and glucans on surface of dermatophytes. Their activation initiate a cascade of signals that induce the nuclear factor (NF)-kB and mitogen-activated protein kinase (MAPK) pathways, which in turn stimulate the T-helper (Th) 17 and Th1 cells which play important roles in the host immune response|
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DC-SIGN (CD209) is an important PRR and is structurally a type II transmembrane protein belonging to the CLR family and recognizes ß-glucan on fungal cell walls., Dectin-2, a CLR expressed in most DC, such as LC, recognizes and binds to M. canis and T. rubrum hyphae, causing the production of pro-inflammatory cytokines like IL-12, IL-10, and TNFα and help present the antigens to CD4+ T cells, promoting their proliferation and release of IL-4, IL-10, and IFN- γ.
Dectin-1 is another CLR that functions as a transmembrane PRR for fungal pathogens through its ability to bind ß-glucan carbohydrates. [Figure 2] Macrophages act as an intermediary of the keratinocyte and dendritic cell-mediated immune responses, and they either kill the fungus or undergo destruction. Toll-like receptor-2 located on the surface of monocytes mediates phagocytosis of conidia as well as promotes the a pro-inflammatory response with the secretion of cytokines such as TNF-α. Downstream signaling and the resultant immune effects are depicted in [Figure 1].
Besides keratinocytes and DC, neutrophils also play a vital role in innate immunity against dermatophytes that accumulate soon after the corneocyte adherence to the conidia during germination. Neutrophils, along with macrophages, are thought to be the final effector cells in eliminating dermatophytosis and the mediator of intra and extracellular lysis of dermatophytes both via the oxidative pathway and release of TNF-α., A fungal hydrophobin, released following induction of the expression of hypA gene following interaction of A. benhamiae with keratinocytes, renders them less susceptible to neutrophil action.
The contribution of innate immunity in clearing fungal infections was recently corroborated by a paper which showed that Rag2-/- mice, which lack T and B cells, can ultimately clear the dermatophyte infection. Also, a study in immunocompetent wild-type mice showed that even there was only a modest reduction in the fungal load in a secondary infection versus a primary one, suggesting that innate immunity plays the major role in the immune responses against fungi.
Expression of IL–17 as early as three days after a dermatophyte infection means that there is a rapid activation of IL–17 is reminiscent of the innate Th-17 responses against fungal infections rather than adaptive immune response.
Acquired immune response
The comparative role of specific humoral and cellular immune responses against fungal infections has been a debatable conundrum in mycology. While cell-mediated immunity (CMI) is protective against many fungi, including dermatophytes, certain types of antibody responses may also provide protection. CMI also increases epidermal proliferation facilitating dermatophyte elimination. The type of CMI response is critical in determining resistance or vulnerability to fungal infection even though the cytotoxic activity against dermatophytes is seen with both CD4 and CD8 T cells.
Overall, the elimination of a fungal infection is mediated by Th1-type CMI, while Th2 response predisposes to infection or leads to allergic responses. Th1 cells produce cytokines such as IFN- γ and trigger phagocyte stimulation.,,,, In contrast, a Th2- response results in enhanced production of antibodies and IL-4, IL-5, and IL-13., IL- 4 mediates IgE production by B cells while IL-5 helps in eosinophil recruitment via vascular cell adhesion molecule (VCAM)-very late antigen (VLA)-4 adhesion molecule pathway and enhances eosinophil production from the bone marrow.
It has been shown that initially, IFN- γ level is low along with high levels of IL-10, which inhibit Th1 response. Over time, IL-10 production decreases, while the levels of IFN- γ increase. Thus, apart from inducing a Th2-type response, IL-10 plays a significant role in innate immunity and immune response regulation. IL-10 prevents a damaging inflammatory response by blocking excessive production of TNF-α and other cytotoxic metabolites, enabling the development of a specific immune response. Interestingly, in a murine model study, the levels of IL-10 were notably higher during the early stage of the infection.
Recently, the focus has shifted to the Th17 cell pathway, which promotes the Th1-type immune responses and inhibits Th2-type responses. IL-17A has been shown to mobilize neutrophils and stimulate defensins' secretion, contributing to the rapid and effective control of infection as an innate response.,
The earlier studies on cytokine profile at the dermatophyte infection site reveals TGF-ß, IL-1ß, and IL-6, which are involved in the initiation and perpetuation of the Th17 pathway. Further, an increase in IL-22 mRNA was also observed in experimental models, both findings suggesting that the Th17 cell pathway may be involved in the immunopathogenesis of dermatophytic infections.
In more recent studies, these hypotheses have been tested and validated, and the protective role of the Th17 pathway has now clearly emerged. Heinen et al. recently reported that with dermatophytic infections, the adaptive immunity is polarized to both Th1 and Th17 responses, with dermatophyte clearance mediated by the Th17 antifungal response and the Th1 response being involved in fungal clearance as well as the down-modulation of Th17 induced inflammation. Also, a study revealed that it may exert antifungal activity by enhancing the epidermal barrier function. In fact, cytokines IFN-γ and IL-17A, signature cytokines of Th1 and Th17 lineages, respectively, are needed for optimal protection to the disease. Moreover, the authors found that IL–17 and IFN-γ show complementary immunological effects during the resolution of T. benhamiae infection. However, in contrast to these findings, Rai et al. demonstrated high Th17 and T-reg expression in peripheral blood of patients with chronic skin dermatophytoses, suggesting a complex interplay of T cell lineages in causing disease persistence. A summary of the role of Th cells is listed in [Table 2]. Here it is pertinent to point out that T Reg cells may effect a variety of sequels ranging from protective tolerance (defined as a host response that safeguards host's survival through a trade-off between sterilizing immune responses and their negative regulation, which limits pathogen elimination) to overt immunosuppression.
Interestingly, the severity of the inflammatory reaction depends on the depth of skin invasion, which is largely determined by proteases. It has been proposed that dermatophytes that are weakly invasive elude soluble or cellular components of the immune system by residing in the superficial non-living skin layers. Specific immunogenic properties of the secreted proteases may also effect immune defenses. Notably, proteases 'subtilisin' from T. rubrum (Tri r2) and 'dipeptidyl-peptidase V' from Trichophyton tonsurans (Tri t 4) can modulate the immune responses., Also, the surface antigen subtilisin Sub1 of T. rubrum has also been proposed to play a role in immune-modulation. Moreover, Trichophyton rubrum cell wall mannans may be a cause of dose-dependent immunosuppression and inhibit the in vitro lymphoproliferative response and stratum corneum turnover either directly or by altering lymphocyte function.
Acute dermatophytosis is associated with a delayed-type hypersensitivity (DTH) response to trichophyton and blastogenic response of T lymphocytes with progression to healing, while persistent disease corresponds to inadequate cellular immune responses with immediate hypersensitivity (IH) responses, high levels of IgE and IgG4 antibodies, and of Th2 cytokines released by mononuclear leukocytes., Furthermore, chronic dermatophytosis, due to association with IH and Th2 cytokines, may underlie the pathogenesis of allergic diseases, mainly asthma.
Though it is largely believed that the immune response to dermatophytes is DTH-dependent, there are contrarian findings. In AIDS, the incidence of invasive dermatophytoses is expected to be higher due to reduced CD4 + T lymphocyte counts. However, this is not seen in practice while it is more frequent in non-AIDS immunocompromised patients, suggesting different immunological mechanisms play a role.,, Furthermore, patients with chronic dermatophytosis may have DTH against trichophyton.
| Host Dependent Factors|| |
Susceptibility to dermatophytosis is variable. The risk factors favoring dermatophytosis include defective epidermal and immunological barriers., Individual susceptibility factors are still unclear but include alteration in sebum fatty acids, presence of moisture or transferrin, and other inhibitors for the dermatophyte growth in sweat or serum and skin, including carbon dioxide concentration.,
An impaired epidermal barrier aggravated by scratching, atopy, ichthyosis, low level of sebum secretion before puberty, and possibly elevated environmental humidity, may promote dermatophytosis.,, Impaired peripheral blood circulation with concomitant diminished nutrient availability, reduced oxygenation, and delay in the relocation of immune-competent cells or release of antimicrobial peptides (AMP) at infection site may also increase the susceptibility for infections. Diabetes predisposes to an almost three-fold increased chance of dermatophytosis, especially foot and nail tinea, due to altered peripheral blood circulation and nerve endings. Further, extensive and invasive infections have been reported in various underlying conditions such as patients with atopic dermatitis, leukemia or lymphoma, diabetes, hepatitis B and C related cirrhosis, on haemodialysis for renal failure, alcoholic liver disease, congenital adrenal hyperplasia, Cushing disease, patients on immunosuppressants/modulators for systemic lupus erythematosus, psoriasis, rheumatoid arthritis, Behcet's disease, autoimmune hepatitis and myasthenia gravis.,,
It is important to note here that topical steroid use disturbs the local immune function and severely impairs the clearing of the fungi from the skin. The crucial effects on local immunity are detailed in [Table 3].,
|Table 3: The effect of corticosteroids on various steps involved in pathogenesis of dermatophytosis|
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Lastly, various genetic predisposition factors have been identified, and certain HLA haplotypes predict increased risk of dermatophyte infections, particularly HLA-DR8 has been shown to increase susceptibility for onychomycosis. Mutations in gene CLEC7A, which encodes protein dectin-1 that binds to fungal ß-glucans, as well as mutations in the genes of signaling pathways such as CARD9 and STAT3, engaged in the antifungal immune response, are associated with an increased incidence of dermatophytosis. Low copy numbers of gene DEFB4, encoding the antimicrobial peptide (AMP) ß-defensin-2, also increase vulnerability to dermatophytosis.
| Clinical Implications|| |
It is obvious that the immunological interaction of the host immune response and the fungi determine the clinical sequelae. Thus, understanding of the complex immune responses to Trichophyton spp is essential for developing adequate therapeutic strategies for treating chronic tinea infections. It has been estimated that about a fifth of all T. rubrum infections are chronic. T.mentagrophyte/interdigitale complex, which is currently the prevalent strain causing dermatophytoses in India, also seems to subvert host immunity, though the precise mechanisms are not known at present. It is known that chronic infections with T. rubrum can invade the deeper levels of the epidermis, yet suppressing an immune response, and prolonging symptoms such as mild to intense itch, scaling, and development of plaques. These chronic infections often do not respond to treatment, having severe implications for the patients.
- Chronic or relapsing dermatophytic infections in immunocompetent individuals are related to the prevalence of immediate hypersensitivity mediated by IgE (immunoglobulin E) to the fungus, as well as high serum levels of IgE and IgG4 (immunoglobulin G4). T. rubrum produces substances, e.g., the mannans associated with glycoproteins that decrease the immune response, thus preventing complete eradication of the fungus. Anthropophilic species induce immune-suppression through toll-like receptor 2 (TLR2) mediated IL-10 release, with consequent generation of CD4+ CD25+ T-regulatory cells with immunosuppressive potential. Consequently, there is increased Th2-type responses that is inadequate to fight fungal infections leading to chronic and extensive infection. Moreover, a study showed that macrophages and neutrophils have reduced T rubrum phagocytosis and downstream cytokine release in patients with chronic dermatophytoses.
Also, the release of H2O2 and NO and T rubrum killing activity of these cells was reduced in these patients and was normal in patients with acute tinea pedis infections suggesting Trichophyton-specific functional defects in patients with chronic dermatophytoses. The fungal cell wall mannans can inhibit DC-SIGN-dependent cell adhesion to ICAM-3 of wild-type T cells, thereby decreasing the initial interactions between DC and wild-type T cells, thus blocking antigen presentation and activation of T cells, favoring the development of invasive or disseminated infections caused by dermatophytes. The clinical correlate of this is the leathery, lichenified lesions seen in some patients, and this is a surrogate clinical sign of chronicity.
- The use of immunosuppression via oral agents or topical steroid abuse can subvert almost all aspects of the host immune response. [Table 3] Dermatophytes can invade the dermal tissue, particularly after local trauma in patients with chronic infections. In immune-deprived patients, dermatophytosis may involve the subcutaneous tissues and even deep organs, possibly becoming a life-threatening disease in the absence of appropriate treatment.
- A combination of impaired peripheral blood circulation, reduced oxygenation, and delay in migration of immune-competent cells or production of antimicrobial peptides (AMP) at the site of infection may favor the infectious process, which explains the 3X increased risk of dermatophytosis, especially foot and nail tinea in diabetes.
- A deranged barrier can lead to recurrences, hence epidermal barrier integrity is a crucial aspect that can determine a chronic infection.,,
- The pH of skin is important, and an alkaline pH can potentiate the virulence of the dermatophyte species.,,,,, Thus, the aggressive use of soaps can prove to be detrimental to the host defense, and thus the use of these products has no scientific rationale. Moreover, providing sub-optimal concentrations of antifungals at the infection site can promote further resistance. The acidic pH of skin is important to maintain the stratum corneum barrier function and thus acts as a resistance to invasion by dermatophytes. It has been demonstrated that the skin pH at the site of infection in tinea pedis is higher than the normal skin pH. A higher pH has also been demonstrated in the intertriginous regions of diabetic patients, providing a possible explanation for a higher incidence of candidal infections involving these sites. The use of a syndet bar would help in maintaining the barrier function and a protective pH to withstand the infection with dermatophytes, and may thus be recommended.
- The spread between family members, suggests (though it has not been scientifically proven) that the prevalent strain is transmitted through fomites. It is prudent to advise washing clothes at high temperatures (=60°C) as it is likely to be beneficial based on the results of in vitro experiments on various dermatophytes.
- A study on T. rubrum showed that the SLC11A1, RNASE7, and CSF2 genes were stimulated, and their products play a role in signaling and migration of immune cells and have potential antimicrobial activity. RNASE7 encodes for ribonuclease 7, which is part of the keratinocyte innate defense mechanisms. CSF2 encodes for granulocyte-macrophage colony-stimulating factor (GM-CSF), which is involved in recruiting immune cells to the site of infection and is part of the host innate immune response. SLC11A1 gene encodes an integral membrane protein involved in actuating macrophages and causing several effects on the signaling of the innate immune system such as TNFα, IL1-ß, among others. Genes that are involved in the maintenance of epithelial barrier integrity such as FLG and KRT1 were inhibited. This study revealed that modulation of the genes involved in T. rubrum-host interaction could signify possible targets for the management of dermatophytoses. Also, products that target Heat shock protein 90 (Hsp90) can also be used to treat T. rubrum infections.
| Conclusions|| |
Studies on antifungal resistance in dermatophytes lag far behind those available for systemic fungi. With increasing reports of resistance to terbinafine, the use of azoles (specifically itraconazole) for dermatophytoses is on an upward trend., Even though Indian dermatologists have found that the western recommendations on the use of itraconazole for tinea corporis/cruris are proving inadequate to eradicate infections and thus higher doses and longer durations of treatment are being suggested, the MIC data and existing data on skin pK of antifungal drugs, reliably predicts efficacy to azoles.,,
Almost all studies show sensitivity to itraconazole, implying that the solution to recalcitrant infection might need a synergism of antifungal drugs with the host immune response to clear the fungi.,,, Discovering the means by which the species evade the innate host defense and bypass the cellular immune response is the key to emerging effectual antifungal therapeutic modalities. More efficacious treatment for chronic dermatophytoses would therefore include aiming at the mechanisms by which the species restricts the immune response, such as the mechanism by which it inhibits TLRs, and finding a way to reestablish the cell-mediated immune response, such as reviving the macrophages phagocytic activity. Also, drugs that target the various virulence factors can help in treating dermatophytosis.
Here it is important to emphasize that although there is some experimental reasoning on the ability of T.rubrum to cause chronic minimally inflammatory disease, the presently prevalent species (T.interdigitale) barely has any such data to its credit. Thus, there is an emergent need to study the virulence factors of the prevalent strain. In essence, understanding the interaction of the immune response with the dermatophyte, can help supplant and supplement the existing pharmacological remedies that fail in recalcitrant dermatophytoses.
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| References|| |
Singh A, Masih A, Khurana A, Singh PK, Gupta M, Hagen F et al
. High terbinafine resistance in Trichophyton interdigitale isolates in Delhi, India harbouring mutations in the Squalene epoxidase (SQLE) gene. Mycoses 2018; 61:477-484
Sardana K, Khurana A. Overview of Causes and Treatment of Recalcitrant Dermatophytoses. In: IADVL Manual on Management of Dermatophytoses (Sardana K, Khurana A, Garg S, Poojary S eds), 1st
ed.n. Delhi: CBS,2018:80-105.
Rudramurthy SM, Shankarnarayan SA, Dogra S, Shaw D, Mushtaq K, Paul RA et al
. Mutation in the Squalene epoxidase gene of Trichophyton interdigitale and Trichophyton rubrum associated with allylamine resistance. Antimicrob Agents Chemother 2018; 62:e02522-17.
Dabas Y, Xess I, Singh G, Pandey M, Meena S. Molecular identification and antifungal susceptibility patterns of clinical dermatophytes following CLSI and EUCAST guidelines. J Fungi. 2017;3:E17.
Preuett BL, Schuenemann E, Brown JT Kovac ME, Krishnan SK, Abdel-Rahman SM. Comparative analysis of secreted enzymes between the anthropophilic- zoophilic sister species Trichophyton tonsurans and Trichophyton equinum. Fungal Bio.l 2010;114:429-37.
Giddey K, Monod M, Barblan J, Potts A, Waridel P, Zaugg C. et al
. Comprehensive analysis of proteins secreted by Trichophyton rubrum and Trichophyton violaceum under in vitro
conditions. J Proteome Res2007;6:3081-92.
Corzo-León DE, Munro CA, MacCallum DM. An ex vivo Human Skin Model to Study Superficial Fungal Infections. Front Microbiol. 2019;10:1172.
MacGregor JM, Hamilton A, Hay RJ. Possible mechanisms of immune modulation in chronic dermatophytosis-an in vitro
study. Br J Dermatol 1992;127:233-8.
Hay RJ. Dermatophytosis and other superficial mycosis. In: Principles and practice of infectious diseases (Mandell GL, Bennett JE, Dolin R eds), 4th
ed.n. New York: Churchill-Livingstone; 1995: 2375-86.
Baldo A, Mathy A, Tabart J, Camponova P, Vermout S, Massart L, et al
. Secreted subtilisin Sub3 from Microsporumcanis is required for adherence to but not for invasion of the epidermis. Br J Dermatol 2010;162:990-7.
Monod M, Lechenne B, Jousson O, Grand D, Zaugg C, Stöcklin R, et al
. Aminopeptidases and dipeptidyl-peptidases secreted by the dermatophyte Trichophyton rubrum. Microbiology 2005;15:145-55.
Duek L, Kaufman G, Ulman Y, Berdicevsky I. The pathogenesis of dermatophyte infections in human skin sections. J Infect 2004;48:175-80.
Kaufman G, Horwitz BA, Duek L, Ullman Y, Berdicevsky I. Infection stages of the dermatophyte pathogen Trichophyton: Microscopic characterization and proteolytic enzymes. Med Mycol 2007;45:149-55.
Faway É, Cambier L, Mignon B, Poumay Y, Lambert de Rouvroit C. Modeling dermatophytosis in reconstructed human epidermis: A new tool to study infection mechanisms and to test antifungal agents. Med Mycol 2017;55:485-494.
Faway É, Lambert de Rouvroit C, Poumay Y. In vitro
models of dermatophyte infection to investigate epidermal barrier alterations. Exp Dermatol 2018;27:915-22.
Peres NT, Maranhão FC, Rossi A, Martinez-Rossi NM. Dermatophytes: Host-pathogen interaction and antifungal resistance. An Bras Dermatol 2010;85:657-67.
Sharma A, Chandra S, Sharma M. Difference in keratinase activity of dermatophytes at different environmental conditions is an attribute of adaptation to parasitism. Mycoses 2012;55:410-5.
Jensen JM, Pfeiffer S, Akaki T, Schröder JM, Kleine M, Neumann C et al
. Barrier function, epidermal differentiation and human b-defensin 2expression in tinea corporis. J Invest Dermatol 2007;127:1720-7.
Grumbt M, Monod M, Yamada T, Hertweck C, Kunert J, Staib P. Keratin degradation by dermatophytes relies on cysteine dioxygenase and a sulfite efflux pump. J Invest Dermatol 2013;133:1550-5.
Martinez-Rossi NM, Peres NT, Rossi A. Pathogenesis of Dermatophytosis: Sensing the Host Tissue. Mycopathologia 2017;182:215-227.
Orejas M, Espeso EA, Tilburn J, Sarkar S, Arst HN, Penalva MA. Activation of the Aspergillus PacC transcription factor in response to alkaline ambient pH requires proteolysis of the carboxy-terminal moiety. Genes Dev 1995;9:1622-32.
Maccheroni W Jr, May GS, Martinez-Rossi NM, Rossi A. The sequence of palF, an environmental pH response gene in Aspergillus nidulans. Gene 1997; 194:163-7.
Calcagno-Pizarelli AM, Negrete-Urtasun S, Denison SH, Rudnicka JD, Bussink HJ, Múnera-Huertas T et al
. Establishment of the ambient pH signaling complex in Aspergillus nidulans: PalI assists plasma membrane localization of PalH. Eukaryot Cell 2007;6:2365-75.
Galindo A, Hervas-Aguilar A, Rodriguez-Galan O, Vincent O, Arst Jr HN, Tilburn J et al
. PalC, one of two Bro1 domain proteins in the fungal pH signalling pathway, localizes to cortical structures and binds Vps32. Traffic 2007;8:1346-64.
Hervas-Aguilar A, Rodriguez JM, Tilburn J, Arst HN Jr, Pen˜alva MA. Evidence for the direct involvement of theproteasome in the proteolytic processing of the Aspergillusnidulans zinc finger transcription factor PacC. J BiolChem 2007;282:34735-47.
Galindo A, Calcagno-Pizarelli AM, Arst HN Jr, Penalva MA. An ordered pathway for the assembly of fungalESCRT-containing ambient pH signalling complexes atthe plasma membrane. J Cell Sci 2012;125:1784-95.
Jacob TR, Peres NT, Martins MP, Lang EA, Sanches PR, Rossi A, et al
. Heat shock protein 90 (Hsp90) as a molecular target for the development of novel drugs against the dermatophyte Trichophyton rubrum. Front Microbiol 2015;6:1241.
Gupta AK, Ahmad I, Borst I, Summerbell RC. Detection of xanthomegnin in epidermal materials infected with Tricho-phyton rubrum. J Invest Dermato. 2000;115:901-5.
Lopez-Martinez R, Manzano-Gayosso P, Mier T, Mendez-Tovar LJ, Hernandez-Hernandez F. Exoenzymes of dermatophytes isolated from acute and chronic tinea. Rev Latinoam Microbiol 1994;36:17-20.
Almeida SR. Immunology of dermatophytosis. Mycopathologia 2008;166:277-83.
Brilhante RS, Correia EE, Guedes GM, de Oliveira JS, Castelo-Branco DD, Cordeiro RD et al
. In vitro
activity of azole derivatives and griseofulvin against planktonic and biofilm growth of clinical isolates of dermatophytes. Mycoses 2018;61:449-454.
Underhill DM, Iliev ID. The mycobiota: Interactions between commensal fungi and the host immune system. Nat Rev Immunol. 2014;14(6):405-416.
Willment JA, Brown GD. C-type lectin receptors in antifungal immunity. Trends Microbiol 2008;16:27-32
Sugita K, Kabashima K, Atarashi K, Shimauchi T, Kobayashi M, Tokura Y. Innate immunity mediated by epidermal keratinocytes promotes acquired immunity involving Langerhans cells and T cells in the skin. Clin Exp Immunol 2007;147:176-83.
Nakamura Y, Kano R, Hasegawa A, Watanabe S. Interleukin-8 and tumor necrosis factor alpha production in human epidermal keratinocytes induced by Trichophyton mentagrophytes. ClinDiagn Lab Immunol 2002;9:935-7.
Shiraki Y, Ishibashi Y, Hiruma M, Nishikawa A, Ikeda S. Cytokine secretion profiles of human keratinocytes during Trichophyton tonsurans and Arthroderma benhamiae infections. J Med Microbiol. 2006;55:1175-1185.
Ogawa H, Summerbell RC, Clemons KV, Koga T, Ran YP, Rashid A et al
. Dermatophytes and host defence in cutaneous mycoses. Med Mycol 1998;36:166-73.
Deng W, Liang P, Zheng Y, Su Z, Gong Z, Chen J et al
. Differential gene expression in HaCaT cells may account for the various clinical presentation caused by anthropophilic and geophilic dermatophytes infections. Mycoses. 2020;63(1):21-29.
Koga T, Ishizaki H, Matsumoto T, Hori Y. In vitro
release of interferon-gamma by peripheral blood mononuclear cells of patients with dermatophytosis in response to stimulation with trichophytin. Br J Dermatol 1993;128:703-704.
Bressani VO, Santi TN, Domingues-Ferreira M Almeida A, Duarte AJ, Moraes-Vasconcelos D. Characterization of the cellular immunity in patients presenting extensive dermatophytoses due to Trichophyton rubrum. Mycoses 2013;56:281-288.
Mignon B, Tabart J, Baldo A, Mathy A, Losson B, Vermout S. Immunization and dermatophytes. CurrOpin Infect Dis 2008;21:134-40.
Tani K, Adachi M, Nakamura Y, Kano R, Makimura K, Hasegawa A, et al
. The effect of dermatophytes on cytokine production by human keratinocytes. Arch Dermatol Res 2007;299:381-7.
Reis APC, Correia FF, Jesus TM, Pagliari C, Sakai-Valente NY, Belda Júnior W et al
. In situ
immune response in human dermatophytosis: Possible role of Langerhans cells (CD1a+) as a risk factor for dermatophyte infection. Rev Inst Med Trop Sao Paulo. 2019;61:e56.
Sato K, Yang XL, Yudate T, Chung JS, Wu J, Luby-Phelps K et al
. Dectin-2 is a pattern recognition receptor for fungi that couples with the Fc receptor gamma chain to induce innate immune responses. J Biol Chem 2006;281:38854-66.
Saijo S, Ikeda S, Yamabe K, Kakuta S, Ishigame H, Akitsu A et al
. Dectin-2 recognition of mannans and induction of Th17 cell differentiation is essential for host defense against Candida albicans. Immunity 2010;32:681-91.
Santiago K, Bomfim GF, Criado PR, Almeida SR. Monocyte-derived dendritic cells from patients with dermatophytosisrestrict the growth of Trichophyton rubrumand induce CD4-T cell activation. PLoS One 2014;9(11):e110879.
Brown, G. Dectin-1: A signalling non-TLR pattern-recognition receptor. Nat Rev Immunol. 2006;6:33-43.
Celestrino GA, Reis APC, Criado PR, Benard G, Sousa MGT. Trichophyton rubrum Elicits Phagocytic and Pro-inflammatory Responses in Human Monocytes Through Toll-Like Receptor 2. Front Microbiol. 2019;10:2589.
Brasch J. Current knowledge of host response in human tinea. Mycoses. 2009;52(4):304-12.
Heddergott C, Bruns S, Nietzsche S, Leonhardt I, Kurzai O, Kniemeyer O et al
. The Arthrodermabenhamiae hydrophobin HypA mediates hydrophobicity and influences recognition by human immune effector cells. Eukaryot Cell 2012;11:673-82.
Heinen MP, Cambier L, Antoine N, Gabriel A, Gillet L, Bureau F, et al
. Th1 and Th17 Immune Responses Act Complementarily to Optimally Control Superficial Dermatophytosis. J Invest Dermatol. 2019;139(3):626-637.
Verma AH, Gaffen SL. Dermatophyte Immune Memory Is Only Skin-Deep. J Invest Dermatol. 2019;139(3):517-519.
Woodfolk JA, Platts-Mills TA. The immune response to dermatophytes. Res Immunol 1998;149:436-45.
Waldman A, Segal R, Berdicevsky I, Gilhar A. CD4+ and CD8+T cells mediated direct cytotoxic effect against Trichophyton rubrum and Trichophyton mentagrophytes.Int J Dermatol 2010;49:149-57.
Traynor TR, Huffnagle GB. Role of chemokines in fungal infections. Med Mycol 2001; 39: 41-50.
Al HM, Fitzgerald SM, Saoudian M, Krishnaswamy G. Dermatology for the practicing allergist, Tinea pedis and its complications. ClinMol Allergy 2004;2:5.
Saraiva M, O'garra A. The regulation of IL-10 production by immune cells. Nat Rev Immunol 2010;10:170.
Venturini J, Alvares AM, Camargo MR, Marchetti CM, de Campos Fraga-Silva TF, Luchini AC et al
. Dermatophyte-host relationship of a murine model of experimental invasive dermatophytosis. Microbes Infect 2012;14:1144-51.
Gaffen SL, Hernandez-Santos N, Peterson AC. IL-17 signaling in host defense against Candida albicans. Immunol Res 2011;50:181-187.
Huppler AR, Conti HR, Hernandez-Santos N, Darville T, Biswas PS, Gaffen SL. Role of neutrophils in IL-17 dependent immunity to mucosal candidiasis. J Immunol 2014;192:1745-1752.
Cambier L, Weatherspoon A, Defaweux V, Bagut ET, Heinen MP, Antoine N et al
. Assessment of the cutaneous immune response during Arthrodermabenhamiae and A. vanbreuseghemii infection using an experimental mouse model. Br J Dermatol 2014;170:625-33.
Burstein VL, Guasconi L, Beccacece I, Theumer MG, Mena C, Prinz I et al
. IL-17–Mediated Immunity Controls Skin Infection and T Helper 1 Response during Experimental Microsporum canis Dermatophytosis. J Invest Dermatol. 2018;138(8):1744-53.
Heinen MP, Cambier L, Antoine N, Gabriel A, Gillet L, Bureau F, et al
. Th1 and Th17 Immune Responses Act Complementarily to Optimally Control Superficial Dermatophytosis. J Invest Dermatol. 2019;139(3):626-637.
Rai G, Das S, Ansari MA, Singh PK, Pandhi D, Tigga RA et al
. The interplay among Th17 and T regulatory cells in the immune dysregulation of chronic dermatophytic infection. Microb Pathog. 2020;139:103921.
Heinen MP, Cambier L, Fievez L, Mignon B. Are Th17 Cells Playing a Role in Immunity to Dermatophytosis?. Mycopathologia. 2017;182(1-2):251-261.
Dahl MV, Grando SA. Chronic dermatophytosis: What is special about Trichophyton rubrum? AdvDermatol 1994;9:97-109.
Beauvais A, Monod M, Wyniger J, Debeaupuis JP, Grouzmann E, Brakch N et al
. Dipeptidyl-peptidase IV secreted by Aspergillus fumigatus, a fungus pathogenic to humans. Infect Immun1997;65:3042-7.
Woodfolk JA, Sung SS, Benjamin DC, Lee JK, Platts-Mills TA. Distinct human T cell repertoires mediate immediate and delayed-type hypersensitivity to the Trichophyton antigen, Tri r 2. J Immunol 2000;165:4379-87.
Woodfolk JA, Wheatley LM, Piyasena RV, Benjamin DC, Platts-Mills TA. Trichophyton antigens associated with IgE antibodies and delayed type hypersensitivity. Sequence homology to two families of serine proteinases. J Biol Chem1998;273:29489-96.
Woodfolk JA. Allergy and dermatophytes. Clin Microbiol Rev. 2005;18:30-43.
Marconi VC, Kradin R, Marty FM, Hospenthal DR, Kotton CN. Disseminated dermatophytosis in a patient with hereditary hemochromatosis and hepatic cirrhosis: Case report and review of the literature. Med Mycol 2010; 48:518-27.
Hay RJ, Baran R. Deep dermatophytosis: Rare infections or common, but unrecognised, complications of lymphatic spread?. Curr Opin Infect Dis 2004; 17:77-9.
Koga T. Immune surveillance against dermatophyte infection. In: Fungal Immunology: From an Organ Perspective (Fidel PL, Huffnagle GB eds), 1st
edn. New York, Springer; 2005:443-452.
Calderon RA.Immunoregulation in dermatophytosis. Crit RevMicrobiol 1989;16:339-68.
Gupta AK, Konnikov N, MacDonald P, Rich P, Rodger NW, Edmonds MW et al
. Prevalence and epidemiology of toenail onychomycosis in diabetic subjects: A multicentre survey. Br J Dermatol 1998;139:665-71.
King RD, Khan HA, Foye JC, Greenberg JH, Jones HE. Transferrin, iron, and dermatophytes. I. Serum dermatophyte inhibitory component definitively identified as unsaturated transferrin. J Lab Clin Med 1975; 86:204-12.
Rouzaud C, Hay R, Chosidow O, Dupin N, Puel A, Lortholary O, et al
. Severe dermatophytosis and acquired or innate immunodeficiency: A review. J Fungi 2015;2:4.
Flammer JR, Rogatsky I. Minireview: Glucocorticoids in autoimmunity: Unexpected targets and mechanisms. Mol Endocrinol 2011;25:1075-86.
Elenkov IJ. Glucocorticoids and the Th1/Th2 balance. Ann N Y Acad Sci 2004; 1024:138-46.
García-Romero MT, Granados J, Vega-Memije ME, Arenas R. Analysis of genetic polymorphism of the HLA-B and HLA-DR loci in patients with dermatophytic onychomycosis and in their first-degree relatives. Actas Dermosifiliogr (English Edition). 2012;103(1):59-62.
Glocker EO, Hennigs A, Nabavi M, Schäffer AA, Woellner C, Salzer U, et al
. A homozygous CARD9 mutation in a family with susceptibility to fungal infections. N Engl J Med 2009;361:1727-35.
Jaradat SW, Cubillos S, Krieg N, Lehmann K, Issa B, Piehler S, et al
. Low DEFB4 copy number and high systemic hBD-2 and IL-22 levels are associated with dermatophytosis. J Invest Dermatol 2015; 135:750-758
Hay RJ, Reid S, Talwet E, Macnamara K. Immune responses of patients with tinea imbricata. Br J Dermatol 1983;108:581-9.
Dahl MV. Suppression of immunity and inflammation by products produced by dermatophytes. J Am AcadDermatol. 1993; 28: S19-S23.
Netea MG, Sutmuller R, Hermann C, Van der Graaf CA, Van der Meer JW, Van Krieken JH et al
. Toll-like receptor 2 suppresses immunity against Candida albicans through induction of IL-10 and regulatory T cells. J Immunol 2004;172:3712-8.
Sousa MD, Santana GB, Criado PR, Benard G. Chronic widespread dermatophytosis due to Trichophyton rubrum: A syndrome associated with a Trichophyton-specific functional defect of phagocytes. Front Microbiol. 2015;6:801.
Criado PR, Oliveira CB, Dantas KC, Takiguti FA, Benini LV, Vasconcellos C. Superficial mycosis and the immune response elements. An Bras Dermatol 2011;86:726-31.
Smith KJ, Neafie RC, Skelton III HG, Barrett TL, Graham JH, Lupton GP. Majocchi's granuloma. J Cutan Pathol 1991;18:28-35.
Squeo RF, Beer R, Silvers D, Weitzman I, Grossman M. Invasive Trichophyton rubrum resembling blastomycosis infection in the immunocompromised host. J Am Acad Dermatol 1998;39:379-80.
Gupta AK, Konnikov N, MacDonald P, Rich P, Rodger NW, Edmonds MW et al
. Prevalence and epidemiology of toenail onychomycosis in diabetic subjects: A multicentre survey. Br J Dermatol 1998;139:665-71.
Cowen LE, Sanglard D, Howard SJ, Rogers PD, Perlin DS. Mechanisms of antifungal drug resistance. Cold Spring Harb Perspect Med 2014; 5:a019752.
Ali SM, Yosipovitch G. Skin pH: from basic science to basic skin care. Acta Derm Venereol 2013;93:261-7
Chikakane K, Takahashi H. Measurement of skin pH and its significance in cutaneous diseases. Clin Dermatol 1995;13:299-306.
Yosipovitch G, Tur E, Cohen O. Skin surface pH in intertriginous areas in NIDDM patients. Possible correlation to candidal intertrigo. Diabetes Care 1993; 16: 560-563.
Essien J, Jonah I, Umoh A, Eduok S, Akpan E, Umoiyoho A. Heat resistance of dermatophyte's conidiospores from athletes kits stored in Nigerian University Sport's Center. Acta Microbiol Immunol Hung 2009;56:71-9.
Petrucelli M, Peronni K, Sanches P, Komoto TT, Matsuda JB, Silva WA et al
. Dual RNA-Seq Analysis of Trichophyton rubrum and HaCat Keratinocyte Co-Culture Highlights Important Genes for Fungal-Host Interaction. Genes 2018;9:362.
Rajagopalan M, Inamadar A, Mittal A, Miskeen AK, Srinivas CR, Sardana K et al
. Expert Consensus on The Management of Dermatophytosis in India (ECTODERM India). BMC Dermatol 2018;18:6.
Sardana K, Arora P, Mahajan K. Intracutaneous pharmacokinetics of oral antifungals and their relevance in recalcitrant cutaneous dermatophytosis: Time to revisit basics. Indian J Dermatol Venereol Leprol. 2017;83:730-732
] [Full text]
Sardana K, Kaur R, Arora P, Goyal R, Ghunawat S. Is antifungal resistance a cause for treatment failure in dermatophytosis: A study focused on tinea corporis and cruris from a tertiary centre?. Indian Dermatology Online J. 2018;9:90-95.
[Figure 1], [Figure 2]
[Table 1], [Table 2], [Table 3]