Deciphering the fungal code
Fungal skin infection by dermatophytes is one of the commonest diseases globally. Dermatophyte foot infections (tinea pedis and tinea unguium) are also one of the most common foot disorders seen in clinics with around one-third of European adults suffering from the condition . Despite being treatable for most patients, the prevalence remains high. Moreover, emerging antifungal resistance reported in some countries [2-4] is becoming a potential global threat. In order to keep pace against fungal pathogens, it is important to be able to understand what makes them successful as infecting agents. To be able to study the physiology of dermatophytes, the use of genomics has become a significant advance and tool for studying them. Deciphering the genetic code of the organism enables scientists not only to understand how they function but more importantly, what makes them effective infectious agents. Genes code for proteins and can be switched on and off as required. The complete set of the produced proteins from a genome is known as the proteome.
The dermatophytes are a group of fungi, adapted to living on the skin using hair, skin and nail as their main food source. The group consists of three main genera of fungi - Epidermophyton, Trichophyton and Microsporum. A number of dermatophyte species have been genomically sequenced to date, including the most prevalent foot pathogen – Trichophyton rubrum [5, 6]. Consequently, this should increase the understanding of how they function but more importantly, accelerate the identification of potential target areas for future drug treatments .
In a recent paper , a comprehensive analysis of T rubrum has been undertaken (including its proteome). The pathogen is responsible for the vast majority of fungal foot infections we see in clinic. Infection begins with adherence of the fungal elements to the skin, from which it begins to invade the epidermis. For the organism to survive, it must utilise the cornified cells of the epidermis as a food source. Keratin, generally, is a hard protein, strengthened by numerous (cysteine) disulphide bonds which make it more difficult to degrade. Consequently, dermatophyte attack on the skin begins with the degradation of the sulphur bonds (sulphitolysis) in the epidermal keratins. T rubrum is known to be armed with membrane transporters that facilitate the release of these enzymes . Without this stage, the keratin remains intact and infection is unlikely to proceed. The experimental knockout of the genes encoding the enzymes for this process has shown dermatophyte strains subsequently are unable to infect nail and hair .
From this stage, the dermatophyte is able to produce endo- and exo-proteinases, which reduce the weakened keratin into short peptide chains and amino-acids which it is able to assimilate through its fungal membrane. Dermatophytes, adapted to living on skin, are equipped with a particularly wide range of enzymes for this purpose. Digestion in this way of protein results in the accumulation of nitrogen (as ammonium), which serves to enhance the infection by alkalising the local environment promoting further infection through enhanced fungal enzymatic activity within 48 hours of initial infection. Compounds such as l-alanine, kynurenic acid and cysteine have all been identified as by-products of keratin degradation. Interestingly, kynurenic acid can exert strong immunosuppressive activities on immune cells, suppressing the release of the body’s natural defences such as cytokines and TNF-α. This may explain why T rubrum infection can be so persistent as it is frequently asymptomatic, causing few symptoms and little inflammation .
This work so far offers a valuable insight into how fungal infections establish and how they are maintained but it is just the beginning. Further studies of this kind should be able to offer future directions for antifungal treatment through an increased understanding of the pathology of this very common skin disease.
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