Perspective on animal models of dermatophytosis caused by Trichophyton rubrum

In this issue of Virulence, Yoshikawa et al. described the role of the NLRP3 inflammasome in the response of macrophages to Trichophyton rubrum conidia, as well as the influence of interleukin-1 (IL1) signaling in this interaction. On analyzing bone marrow-derived macrophages (BMDMs), the authors observed reduced IL-1b production in response to T. rubrum conidia in NLRP3¡/¡, ASC¡/¡ and caspase-1/-11¡/¡ cells. They also found that IL-1 signaling was important for delaying hyphal development in fungi, thereby protecting macrophages from destruction by the fungus. These findings yielded new and important perspectives for better understanding of the immunological aspects of T. rubrum infection. Although the authors did not provide in vitro evidence regarding which molecular fungal structures are involved with NLRP3 inflammasome activation, the study provides a novel point of view about this axis of immune responses triggered by T. rubrum infection. They used intraperitoneal infection with T. rubrum conidia and reported fungal recovery from the liver for IL-1R¡/¡ and wild-type (WT) mice, but they did not find a statistical significant difference between the groups at any of the time points evaluated. Lower levels of IL-17 were observed for the IL1R¡/¡ group, leading the authors to suggest the involvement of this pathway in the in vivo infection by T. rubrum.The main concern about this in vivo model is the route of infection, since the occurrence of T. rubrum in deep organs, such as the liver and spleen, is not common, and also because of the lack of histopathological analysis of fungal infection in the liver tissue. This concern culminates in the great question yet to be answered: are the in vitro, ex vivo, and in vivo models of dermatophytosis caused by T. rubrum able to mimic the inflammatory response provided by the human skin against this fungus? Trichophyton rubrum belongs to dermatophytes, a group of filamentous fungi that is composed of 3 genera: Epidermophyton, Microsporum, and Trichophyton. These organisms are also classified according to habitat, into anthropophilic, zoophilic, and geophilic fungi,with Trichophyton rubrum being the most common etiologic agent of dermatophytosis. Dermatophytes are known as keratinophilic fungi because of their predilection to infect keratinized tissues, e.g., skin, nail, hair, and horns, implying that these tissues should be prioritized for the study of the host response. The clinical aspects of lesions are diversified and are a result of the delicate balance between the destruction of the keratin and the inflammatory response, which varies according to the etiologic agent and geographical localization. Morphologically, T. rubrum may present hyaline hyphae, microconidia, and macroconidia in addition to chlamydoconidia and arthroconidia. Moreover, all these components may be involved in the infection, and arthroconidia represent the main infective structure for humans. This unique characteristic of T. rubrum, associated with the fact that it is an anthropophilic fungus, is the first challenge faced by a researcher who wants to study the disease in an animal model. It is difficult to determine the number of viable structures for infection (mainly arthroconidia); therefore, most studies use microconidia as a standard fungal structure for infection of animals. All these issues make the study of T. rubrum difficult and therefore only a small number of researchers have focused on the unknown aspects of fungus-host interactions. Most animal models of dermatophytosis were obtained using zoophilic fungi, such as T. mentagrophytes or Microsporum canis, and guinea pigs are often the animal chosen. Animal models using T. rubrum as the etiologic agent are scarce, and therefore little is known about the fungus-host interactions. Although the guinea pig model has many characteristics in common with human skin, work with guinea pigs has a few drawbacks, such as the difficulty in manipulating the animals and the necessity of a large space for cages (mostly because of the large size of the animal), as well as the most important drawback: the lack of knockout (KO) animals. In contrast, mice are easy to manipulate, are less time-consuming to study, and can be placed in small cages. Notwithstanding the fact that experimental infections on the backs of mice may lead to spontaneous healing in about 4 weeks or more after infection, mice are still a good choice as an animal model. Furthermore, it is easier to obtain KO animals with a mouse model. In this context, different studies support the use of mice for experimental dermatophytosis. A previous study used T. quinckeanum to infect BALB/c mice, demonstrating pathological alterations and adherence of microconidia to keratinocytes within 4 hours of infection. In addition, early infiltration of