Clinical Significance of Dermatophytes and Their Pathogenesis

    


    


    Figure 4: 

    

Dermatophytes can survive solely on outer cornified layers of the skin [11,12]. 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 [11]. Natural infection is acquired by the deposition of viable arthrospores or hyphae on the surface of the susceptible individual [13]. After the inoculation in the host skin, suitable conditions favor the infection to progress through the following stages [14].

Adherence

The kinetics of adherence to the skin or nail surface was investigated in several Trichophyton and Microsporum species, using different experimental models and microscopy techniques. These studies showed a time-dependent increase in the number of adhering spores, followed by germination and invasion of the stratum corneum by hyphae growing in multiple directions. Zurita and Hay [14] observed that maximum adherence of Trichophyton spp. arthroconidia to keratinocytes in suspension occurred within 3–4h. Aljabre et al. [15,16] used stripped sheets of stratum corneum or separate keratinocytes to demonstrate that adherence of Trichophyton mentagrophytes arthroconidia is maximum by 6h and that germination of these spores begins by 4h. In a nail plate model, adherence and germination of T. mentagrophytes arthrospores were observed at 6h and side branches at 16h [17]. The early stages of T. mentagrophytes infection were investigated using skin explants of full epidermis thickness [18]. Adherence was maximum at 12h, germination had started by 24h, and penetration of the stratum corneum occurred after 3 days.

Little is known about the factors that mediate adherence of dermatophytes. The ability of T. rubrum to adhere to epithelial cells has been attributed to carbohydrate-specifi c adhesins, expressed on the surface of microconidia [19]. From a morphological point of view, fi brillar projections have been observed in T. mentagrophytes during the adherence phase [20,21]. At the skin surface, long and sparse fi brils 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 [21]. Based on the fi ndings made in the yeast Candida albicans, where secreted aspartic proteases (Saps) have been shown to play a fundamental role in fungal adherence to epithelia [22,23], so that is dermatophytic-secreted proteases could facilitate or even be necessary for effi cient adherence. We have cheched the expression patteren of Exoprotease and Endoprotease genes with their non-protease genes in real time PCR from that data we hypothsised that the Endoprotease have majorly expressed in dermatophytic patient during infection.

Penetration

Dermatophytes are provided with an arsenal of proteases aimed at the digestion of the keratin network into assimilable oligopeptides or amino acids [24]. 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 [24,25]. A direct relationship between keratinases and pathogenicity was established by Viani et al.The protease production in T. rubrum is highly host specific showing reduced physiological activity when growing on their preferred host [26,27].

Immunity Behind Dermatophytic Infection

Development of Host Response

Fungal metabolic products diffuse through the malphigian layer to cause erythema, vesicle or even pustule formation along with pruritus. There in vivo activity is restricted to the zone of differentiation, newly differentiated keratin and Adamson’s fringe within the hair shaft [28]. 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 [29].

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-a secretion from type 1 T-helper lymphocytes and by some key cytokines like interferon-? (IFN-?). 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. 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 [30]. 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 [31]. 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 [32]. Rivalier showed that a dermatophytic infection in humans results in a relative resistance to subsequent infection [33] mainly by the inflammatory forms (kerion), caused by zoophilic species, but not always follow the more chronic anthropophilic infections [18,34]. Barlow and Chattaway [34] 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. It demonstrate such acquired immunity in experimental T. rubrum infection of smooth skin [19,35].

Hypersensitivity ("Trichophytin" Reaction)

Dermatophytid reactions (4–5% of patients) are inflammatory eczematous allergic skin reactions at sites distant from primary fungal infection [36]. 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 [36,37].

Treatment

The treatment is chosen based on the infection site, etiological agent and penetration ability of the drug. The penetration ability and retention in the site of infection of the agent determines its efficacy and frequency of utility. Since the dermatophytes reside in the stratum corneum especially within the keratinocytes, the antifungal agents should have a good penetrating ability. The duration of treatment mainly depends on the type of infection and symptom. Generally a two-three week treatment is required for skin lesions whereas four-six week for feet inflammation [38].

The year 1970 saw the release of Miconazole, the first in the line of azoles group. Since then many more were subsequently synthesized and added to this list during the same period. These antimycotic drugs belonged to the Azoles class of antifungal drugs. The major target of the azoles unlike the other antifungal agents is the cytochrome P450 enzyme [39] (Figure 5).

    


    


    Figure 5: Ergosterol Biosynthesis Pathway.