Pathogenesis of dermatophytoses.

Dermatophytes can survive solely on outer cornified layers of the skin. The ability of certain fungi to adhere to particular host arises from numerous mechanisms and host factors, including the ability to adapt to the human body. Natural infection is acquired by the deposition of viable arthrospores or hyphae on the surface of the susceptible individual. After the inoculation in the host skin, suitable conditions favor the infection to progress through the stages of adherence and penetration. Development of host response is mostly by a T-cell mediated response of delayed-type hypersensitivity. Antibody formation does not seem to be protective. Natural defenses against dermatophytes depend on both immunological and nonimmunological mechanisms.

Introduction

Dermatophytes can survive solely on outer cornified layers of the skin.[12] The ability of certain fungi to adhere to particular host arises from numerous mechanisms and host factors, including the ability to adapt to the human body.[1] Natural infection is acquired by the deposition of viable arthrospores or hyphae on the surface of the susceptible individual.[3] After the inoculation in the host skin, suitable conditions favor the infection to progress through the following stages.[4]

Adherence

After overcoming obstacles (ultraviolet light, temperature, and moisture variation) and competing with the normal flora and sphingosines produced by keratinocytes and the fatty acids produced by the sebaceous glands, the arthroconidia (infectious element) adhere to the keratinized tissue.[4] The germination of arthroconidia and hyphal growth adherence proceeds radially in multiple directions.[56] Little is known about the factors that mediate adherence of dermatophytes; however, it has been hypothesised that dermatophytic-secreted proteases could facilitate or even be necessary for efficient adherence. The ability of Trichophyton rubrum to adhere to epithelial cells has been attributed to carbohydrate-specific adhesins, expressed on the surface of microconidia. From a morphological point of view, fibrillar projections have been observed in T. mentagrophytes during the adherence phase. At the skin surface, long and sparse fibrils connect fungal arthroconidia to keratinocytes and to each other, while in the inner skin layers, newly formed arthroconidia show thin and short appendices covering their entire surface; the latter begin to vanish as a large contact area is established between conidia and skin tissue.[5]

Penetration

Dermatophytes are provided with an arsenal of proteases aimed at the digestion of the keratin network into assimilable oligopeptides or amino acids.[5] Once established, the spores must germinate and penetrate the stratum corneum at a rate faster than desquamation. Penetration is accompanied by dermatophytes secreting multiple serine-subtilisins and metallo-endoproteases (fungalysins) formerly called keratinases that are found almost exclusively in the dermatophytes.[57] A direct relationship between keratinases and pathogenicity was established by Viani et al. However, little information is available about hydrolases, such as lipases, and a ceramidase, produced by these fungi.[5] The mechanism by which mucolytic enzymes, which help in penetration, also provide nutrition to the fungi is unknown.[458] These dermatophytic keratinolytic proteases cannot act before disulfide bridges are reduced within the compact protein network constituting keratinized tissues. This was recently shown to depend from a sulfite efflux pump encoded by the Ssu1 gene. Sulfite excretion by this transporter allows sulfitolysis of proteins, rendering them accessible for proteases, and functions in the same time as a possible detoxification pathway, a future target for new anti-fungal treatments.[5] The protease production in T. rubrum is highly host specific showing reduced physiological activity when growing on their preferred host[910] (Rippon,1988; Rippon and McGinnis,1995). This would explain the well-established anthropophization of these species. Ranganathan reported a similar finding on the relationship between chronicity and low-protease profile of T. rubrum isolates.[11] Fungal mannans in the dermatophyte cell wall have immuno-inhibitory effects and T. rubrum cell wall mannans (TRM) seem to be involved in an immunosuppression phenomenon, inhibiting lymphoproliferative response of mononuclear leukocytes in response to several antigens (dermatophytic or not) and mitogens. Although specific suppressor T cells are eventually activated during persistent infections, target cells for TRM action appear to be monocytes rather than lymphocytes. Trichophyton rubrum mannans may also decrease the keratinocyte proliferation rate, directly or via lymphocyte function alteration, contributing significantly to the chronicity of T. rubrum infection.[45712] However, clinical heterogenicity in substrate preference, with all dermatophyte species invading the stratum corneum of the skin but wide variation in their capacity to invade hair and nail, has been seen.[13]

Development of host response

Fungal metabolic products diffuse through the malphigian layer to cause erythema, vesicle or even pustule formation along with pruritus. Their in vivo activity is restricted to the zone of differentiation, newly differentiated keratin and Adamson's fringe within the hair shaft.[12] Acute dermatophytosis is associated with a DTH skin response against them, while persistent disease corresponds to IH responses, to high levels of IgE and IgG4 antibodies, and to the production of Th2 cytokines by mononuclear leukocytes.[5]

Acquired resistance

The efficient and protective response against dermatophytosis is a cell-mediated response of the DTH, characterized namely by the action of macrophages as effector cells, interferon-α secretion from type 1 T-helper lymphocytes and by some key cytokines like interferon-γ (IFN-γ). Immune detection and chemotaxis occur via low-molecular weight chemotactic factors or alternative complement pathway activation. However, the immune response that is raised, and especially the degree of inflammation, varies according to the dermatophyte species, the host species and the pathophysiological status of the host.[4514] In general, the zoophilic species cause more inflammatory infections, which may heal spontaneously and result in relative resistance to re-infection. The anthropophilic species usually cause more chronic, less circumscribed infections, which result in less resistance to re-infection.[15] Primary infection produces negative trichophytin test and minimal inflammation (mild erythema and scaling) due to increased keratinocyte turnover.

Antibodies

Antibody formation does not seem to be protective.[16] The dermatophyte antigen is thought to be processed by epidermal Langerhans cells and presented in local lymph nodes to T lymphocytes which proliferate, migrate to the infected site, and produce inflammation. The epidermal barrier becomes permeable to transferring and migrating cells leading to spontaneous resolution of lesions. Trichophytin skin test is now positive and clearing of second infection will be more rapid.[4] Rivalier showed that a dermatophytic infection in humans results in a relative resistance to subsequent infection called ‘le phenomene de la reaction acceleree’ or ‘le phenomene de Bruno Bloch’,[17] mainly by the inflammatory forms (kerion), caused by zoophilic species, but not always follow the more chronic anthropophilic infections.[1518] Barlow and Chattaway[18] pointed out that fungi which do not invade the hair follicle do not seem to give rise to an equivalent immunity when growing in the horny layer of the smooth skin. In contrast, Desai et al. could not demonstrate such acquired immunity in experimental T. rubrum infection of smooth skin.[1519]

Hypersensitivity (“Trichophytin” reaction)

Dermatophytid reactions (4–5% of patients) are inflammatory eczematous allergic skin reactions at sites distant from primary fungal infection.[15] Being KOH and culture negative, it is associated with a DTH response to trichophytin test and may involve a local DTH response to systemically absorbed fungal antigen.[1520]

Nonspecific resistance

Natural defenses against dermatophytes depend on immunological and nonimmunological mechanisms.[21] Several host factors like number and activity of sebaceous glands (due to inhibitory effect of sebum on dermatophytes) in a particular body region, breaks in the skin barrier, increased hydration and macerated skin can encourage dermatophyte invasion.[1]

Host factors that help limiting the infection to keratinized tissue include their preference for cooler skin temperatures than the normal body temperature, serum inhibitory factors (beta-globulins, ferritin and other metal chelators) binding to iron essential for growth of dermatophytes.[172223] Unsaturated transferrin inhibits the growth of dermatophytes by binding to the hyphae.[24] A growth modifying, α2 macroglobulin keratin inhibitor, has also been identified in serum.[25] The natural resistance of scalp to T. capitis in adults may be due to post pubertal, fungistatic and fungicidal, long chain saturated fatty acids.[26]

Commensal Pityrosporum yeast aids lipolysis and increases pool of fatty acids available for inhibiting fungi.[22] Humoral immunity has a minor role in acquired resistance to dermatophytoses.[1527]

Invasive dermatophytosis

Invasion or dissemination of dermatophytes within the dermis is rare, but occurs mostly in the setting of a chronic dermatophyte infection (mostly T. rubrum) in an immunosuppressed individual. Acute onset of ulcerating or draining dermal and subcutaneous nodes occurs after hematogenous spread. A more indolent process can occur, presenting most often as tender nodules over extremities.[28-30]

A rare case of a fatal ‘dermatophytic disease’ due to T. Schönleini is also documented in a family of three siblings with a familial immunological defect after eight years of evolution (Hadida et Schousboe).[31]