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Abstract
Trichophyton interdigitale had been regarded as anthropophilic, mainly causing non-inflammatory tinea unguium and tinea pedis. T. mentagrophytes, thought to be zoophilic, were regarded as responsible for more inflammatory dermatophytosis. Indian terbinafine-resistant strains, identified with ribosomal internal transcribed spacer as 'genotype VIII', have recently been termed Trichophyton indotineae based on clinical and mycological features. Some of these have shown selective azole resistance as well. Phenotypic studies have shown some similarities and some differences between Trichophyton indotineae, T. mentagrophytes, and T. interdigitale, which are optimally distinguished with HMG locus analyses as three main genotypic groups containing the type strains of T. indotineae (CBS 146623), T. interdigitale (CBS 428.63), and T.mentagrophytes (IHEM 4268) and having approximate differences in geographic distribution. Trichophyton interdigitale was prevalently isolated from superficial infections on exposed body sites such as the scalp and face, while also feet and nails. Trichophyton mentagrophytes has a similar predilection but are also often found on the trunk and genitals. Trichophyton indotineae is mostly restricted to the trunk and groin. T. indotineae lesions are generally highly inflammatory, strongly associated with tinea cruris, corporis, and faciei and less commonly with fingernail onychomycosis and tinea pedis. They cause papulosquamous, pustular, pseudo-imbricata (tinea faciei), lichenoid, and pityriasis rosea (tinea corporis of the neck) types of lesions and spread rapidly to multiple sites and cause painful lesions with itching or burning. Lipolytic abilities of T. mentagrophytes and T. interdigitale are very similar and are higher than those of T. indotineae, which is associated with a higher prevalence of T. mentagrophytes on the human scalp, which is relatively rich in lipids. Keratin degradation is significantly larger in T. interdigitale due to location (tinea pedis and tinea unguium). Identification of T. indotineae through culture alone may not be sufficient for effective treatment decision-making; genetic analysis for resistance profiles is needed for optimum treatment selection. In India, steroid-induced suppression of local cellular immunity as well as an altered cutaneous microbiome provided a window of opportunity for the unique, multidrug-resistant species Trichophyton indotineae.
Keywords: Anthropophilic, azole, dermatophytosis, geophilic, India, resistance, terbinafine, Trichophyton indotineae, Trichophyton interdigitale, Trichophyton mentagrophytes, zoophilic
Introduction 
Dermatophytoses are one of the most common fungal infections found in humans. It is estimated that 20–25% of the global population may be infected by dermatophytosis, caused by Trichophyton, Microsporum, and Epidermophyton, which are anthropophilic and zoophilic fungi.[1] Dermatophytoses are common in tropical and sub-tropical countries like India.[2]Trichophyton rubrum (anthropophilic dermatophyte) used to be considered the major agent behind dermatophytosis infections in India as well as the world, which is now being replaced by zoophilic T. mentagrophytes.[3],[4] Recurrent, clinically unresponsive dermatophytosis has been encountered very frequently in India in the recent past.[5] Rampant use of topical corticosteroids without prescription in dermatophytic infections seems to have a high contribution to these resistant cases.[6] Studies show that many of the patients have been receiving over-the-counter triple combination of topical steroids with antibiotics and antifungals without a proper diagnosis, especially in North Indian rural regions.[7]T. mentagrophytes and T. interdigitale are being reported as being involved in this epidemic-like scenario in India.[8] Following this finding, the correct identification of the Indian Trichophyton species has become a hotly debated issue. Earlier, T. interdigitale, the anthropophilic variety, was believed to cause non-inflammatory tinea unguium and tinea pedis, while T. mentagrophytes, the zoophilic variety, was thought to be responsible for the more inflammatory dermatophytosis.[9]
Indian strains, identified with ribosomal internal transcribed spacer (rDNA ITS) as genotype VIII of T. mentagtophytes, can be transmitted from human to human (anthropophilic), while their relatively high virulence suggests an animal origin (zoophilic). They have been named T. indotineae for such unique characteristics.[10],[11]
Recently, two terbinafine-resistant strains of T. indotineae based on clinical and mycological features have been identified.[12] This article attempts to elaborate the need for identifying the new species of T. indotineae and how to differentiate it from more commonly known T. mentagrophytes and T. interdigitale.
Background Dermatophytes currently have seven distinct genera. The naming of dermatophyte species has been changing over time, from a morphological and clinical basis to a molecular basis currently, with the aim of having “One fungus=One name”.[13]
Till 2007, T. mentagrophytes was a single morphologically defined species. It included zoophilic variants like T. mentagrophytes variatio granulosum (from rodents or rabbits), var. asteroides (rodents), var. erinacei (hedgehogs), and var. quinckeanum (camels and mice), as well as anthropophilic variants like T. mentagrophytes var. interdigitale, var. goetzii (synonym T. krajdenii), and var. nodulare.[10]
This taxonomy and classification of dermatophytes was revised in 2008 to include genetic characteristics; it also simplified the nomenclature. T. mentagrophytes var. granulosum, var. asteroides, var. interdigitale, var. goetzii, and var. nodulare showed none or single polymorphisms in the used genetic marker (ITS region). They were assigned to the species T. interdigitale. T. erinacei became a separate species as well. T. mentagrophytes, therefore, included only the former var. quinckeanum.[14]
2017 saw another revision in this taxonomy and nomenclature on the basis of morphology, multiple genetic markers, physiology, ecological niche, propagation form, and even genetic markers. Distinct single-nucleotide polymorphisms (SNPs) in the ribosomal internal transcribed spacer (ITS) region were necessary for this nomenclature, which also differentiated anthropophilicity and zoophilicity. Four species, anthropophilic T. interdigitale and zoophilic T. mentagrophytes, T. erinacei, and T. quinckeanum, were decided upon.[15]
In 2015–2017, some unusual, highly terbinafine-resistant isolates of T. interdigitale were reported from cases in Delhi as well as in North India.[16] Point mutations in the SQLE gene in the vital pathway of generating ergosterol (produced amino acid substitutions Phe397Leu in 85% of cases and Leu393Phe in 15%, suspected to alter the C-terminal region of squalene epoxidase that is critical for terbinafine binding) were found.[17]
In 2019, T. mentagrophytes genotypes consistent with GenBank records “KU315316” and “KT192500” representing ITS Type VIII were found in Asia and Oceania.[18] Kano isolated T. indotineae from Japan from fungi from a Nepali and an Indian patient (first isolation of two highly terbinafine-resistant T. interdigitale-like strains, designated NUBS19006 and NUBS19007).[12] Similar strains were isolated from Germany,[10] Denmark,[19] France,[20] and Canada.[21] Many of these infections could be traced to India, but local transmissions from one person to another in the countries mentioned were occurring.[22] It was noted that such infections, though present in multiple countries earlier, showed a steep upward trend after the 2014 outbreak in India, which further demonstrated its origin.[23]
A taxonomy study was done to delineate the new species from the similar T. mentagrophytes and T. interdigitale. The identification process involved an expanded dataset of strains from various continents, utilising a combination of molecular, physiological, and evolutionary parameters. The study analysed a total of 182 strains, consisting of 162 strains from patients, 17 strains from animals, and 3 strains from soil. The strains were collected from various locations, including Europe, India, China, Japan, Australia, and USA. Morphology study and mating experiments were done.[11]
Phenotype Findings The taxonomy study had several findings to differentiate the three species. T. indotineae, T. mentagrophytes, and T. interdigitale all showed expanding, cottony to powdery colonies on Sabouraud dextrose agar (SDA) culture. Colony reverse of T. interdigitale strains showed brown ochre pigmentation, T. mentagrophytes showed brown ochre to pale brown, and T. indotineae showed pale brown to yellow orange. This difference was noted to be statistically significant.[11]
Tween-80 opacity test showed lipolytic activity of T. indotineae to be significantly different from T. mentagrophytes and T. interdigitale (which were indistinguishable).[11]T. mentagrophytes probably showed higher lipolytic activity due to its abundance in human scalp with a high level of sebum.[24]
Other tests also showed corroborating results. Hair perforation was found to be lesser with T. indotineae as compared to others. Keratin azure test results were similar between T. indotineae and T. mentagrophytes but showed increased keratin degradation for T. interdigitale (probably due to its location in nails causing Tinea unguium). Urea hydrolysis test of T. indotineae was different from T. mentagrophytes and T. interdigitale.[11]
Terbinafine and Azole Resistance T. indotineae demonstrates high terbinafine resistance (MIC range 0.0024 to ≥40 lg/ml) due to point mutations of squalene epoxidase gene ERG1, most commonly Phe397Leu and Leu393Phe.[23] A few T. indotineae isolates were also found that contained a c.1342G>A mutation corresponding to Ala448Thr amino acid substitution in ERG1, leading to a variable drug response to allylamines but not contributing significantly to terbinafine resistance (though they were also resistant to fluconazole).[25] 75% of isolates in studies from India have shown terbinafine resistance (MIC ≥0.2 mg/ml) in T. indotineae.[22] Azole resistance has also been noted in T. indotineae due to overexpression of the CYP51B gene encoding sterol 14α-demethylase, though this needs to be studied further.[26]
Genotype Findings As per a previous study, the ITS tree included T. mentagrophytes and T. interdigitale genotypes III, III*, IV, V, VII, VIII, and IX, with 'T. mentagrophytes genotype VIII' already reclassified as a new species, T. indotineae.[27] In the new taxonomy study, nine genotypes were obtained by only ITS analysis from the T. mentagrophytes/T. interdigitale species complex, with T. benhamiae clade, the nearest clade to the T. mentagrophytes/T. interdigitale species complex, selected as outgroup for this taxonomy study.[11]
Different sets of genetic information were combined to understand the evolution of various dermatophyte groups. ITS and Tef1-α (Translation Elongation Factor 1 Alpha) genes along with mating type genes HMG (High Mobility Group) and α-box (Alpha box), which play important roles in the evolution of these groups, were used.
The HMG gene in T. mentagrophytes complex (α-box is present in T. rubrum) denoted two distinct groups corresponding to the genotypes T. mentagrophytes and T. indotineae. However, T. interdigitale could not be clearly separated because of conflicting results across multiple genes (in six strains from animals).
The ITS and Tef1-α trees showed similar patterns, but the ITS locus exhibited higher diversity. The entire genomes of T. mentagrophytes, T. interdigitale, and T. indotineae were found to be very similar to each other, with FastANI values above 95% (ANI values are estimated to assess genetic relatedness among the genomes of the strains).
Most strains of animal origin and from soil were clustered in T. mentagrophytes ITS genotypes III and III*, with few animal origin strains clustering in T. interdigitale (all strains clustered in T. indotineae were from humans). ITS genotypes III, III*, IV, VII, and IX were associated with a single HMG genotype. None of the T. indotineae strains had the α-box gene, suggesting that this species has a clonal outbreak population structure.[11]
Rationale behind the New Nomenclature Though genome analysis showed possible conspecificity (belonging to same species) between the species of T. mentagrophytes, T. interdigitale, and T. indotineae,[11] the clinical emergence of a new type of dermatophyte infection in India necessitates the differentiation of the new T. indotineae species due to its unique recalcitrant, drug-resistant, and virulent nature.[8] Microscopically, T mentagrophytes and T. interdigitale are not distinguishable – molecular identification by polymerase chain reaction (PCR)-based sequencing of the rDNA is needed to distinguish them. T. mentagrophytes ITS genotype VIII, the current predominant pathogen, has been confirmed by ribosomal deoxyribonucleic acid (rDNA) sequencing, considered the gold standard for determining a species.[28]
Unfortunately, the name of this dermatophyte has been wandering in a terminological maze with terms ranging from Trichophyton mentagrophytes, Trichophyton interdigitale, Trichophyton mentagrophytes/Trichophyton interdigitale complex, and, finally, Trichophyton mentagrophytes ITS genotype VIII and Trichophyton indotineae. Due to its emergence and prevalence in India, it has been recently renamed T. indotineae.[28]
Clinical Appearance T. interdigitale was prevalently isolated from superficial infections on exposed body sites such as scalp and face, while also feet and nails were frequently infected with this species. T. mentagrophytes has a similar predilection but is also often found on trunk and genitals. T. indotineae is mostly restricted to trunk and groin.[11]
T. indotineae lesions are generally highly inflammatory. Most cases present with tinea cruris, corporis, and faciei, less commonly with fingernail onychomycosis and tinea pedis. No cases with tinea capitis have been noted, probably due to low lipolytic ability and low penetration into hairs as discussed before. Lesions appear as scaly concentric plaques with red elevated borders with rapid spread to multiple sites. Atypical appearance like papulosquamous, pustular, pseudo-imbricata (tinea faciei), lichenoid, and pityriasis rosea (tinea corporis of the neck) types have been noted. Painful lesions with an itching or burning sensation are common. The disease is often chronic and relapsing despite treatment. Patients who have used steroid locally show signs of atrophy, hypopigmentation, and striae without resolution of the disease.[22],[23]
Slightly different clinical predilections of the species may enhance the differential specialisation in the course of evolution. T. mentagrophytes has long been regarded as zoophilic; however, it can be commonly found in humans. T. indotineae has not been seen from soil. T. interdigitale is anthropophilic in most cases. It is hypothesised that T. mentagrophytes originally was a geophilic or zoophilic, sexual species, from which anthropophilic 'clonal offshoots' T. interdigitale and T. indotineae emerged; genotype III seems closest to the species' original condition.[11]
Management It is important to note that identification of T. indotineae through culture alone may not be sufficient for effective treatment decision-making; genetic analysis for the above-noted resistance profiles is needed for optimum treatment selection.
The first-line drug is itraconazole, which may be needed to continue for 8–12 weeks. Second-line drugs include fluconazole and griseofulvin; terbinafine may be added for a few terbinafine susceptible strains. The choice of topical is luliconazole, and success has been noted with other topical antifungals such as ciclopirox olamine, bifonazole, and miconazole.[22],[23] New agents such as voriconazole have also been effective,[29] as has miltefosine in an in vitro trial.[30]
Hygiene measures such as avoiding body contact and sharing of personal items are to be followed similar to other dermatophytic infections.[22]
State in India Dramatic and rapid epidemiological shift from prevalence of T. rubrum to T. mentagrophytes is being observed in the epidemic-like scenario of dermatophytosis in India. Steroid-induced suppression of local cellular immunity as well as an altered cutaneous microbiome provides a window of opportunity for the unique, multi-drug-resistant species T. indotineae. This has already spread to Bahrain, Canada, Denmark, Finland, France, Germany, Iran, Japan, Russia, and Switzerland. More population-based studies should be done to evaluate the current scenario.
Conclusion T. mentagrophytes, represented by genotypes III, III*, and IV, originally was a geophilic species and is going through a process of adaptation to the human host, releasing several clonal populations with higher degrees of human adaptation. This fungus was soilborne likely from terrestrial burrowing animals; under the conditions of domestication, with novel hosts like guinea pig, chinchilla, cat, and dog, the soilborne part of the life cycle is interrupted, and propagation becomes predominantly clonal. Host switch to humans occurred as the next evolutionary step.
T. indotineae seems quite successful for this kind of adaptation; T. interdigitale may have gone through this process in an earlier stage since it still contains strains carrying both mating types and is not entirely separate from T. mentagrophytes.
We are witnessing an evolution from a geophilic, sexual lifestyle in wild animals, via zoophilicity in domesticated animals, to clonal expansion on humans in successful anthropophilicity, within a single species complex. This has led to the varying and often confusing evolving phenotypic and genotypic characteristics which have confused the nomenclature of these species and especially that of what we now have learnt to identify as T indotineae. The story of this evolutionary process is ongoing.
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