Abstract
Animal models of pathogenic infection are needed to evaluate candidate compounds for the development of anti-infectious drugs. Dermatophytes are pathogenic fungi that cause several infectious diseases. We established a silkworm dermatophyte infection model to evaluate anti-fungal drugs. Injection of conidia of the dermatophyte Arthroderma vanbreuseghemii into silkworms was lethal. A. vanbreuseghemii conidia germinated in liquid culture were more potent against silkworms than non-germinated conidia. Germinated conidia of other dermatophytes, Arthroderma benhamiae, Trichophyton rubrum, and Microsporum canis, also killed silkworms. Injection of heat-treated germinated A. vanbreuseghemii conidia did not kill silkworms, suggesting that only viable fungi are virulent. Injecting terbinafine or itraconazole, oral drugs used clinically to treat dermatophytosis, into the silkworm midgut had therapeutic effects against infection with germinated A. vanbreuseghemii conidia. When silkworms were injected with A. vanbreuseghemii expressing enhanced green fluorescent protein (eGFP), mycelial growth of the fungus was observed in the fat body and midgut. Injection of terbinafine into the silkworm midgut, which corresponds to oral administration in humans, inhibited the growth of A. vanbreuseghemii expressing eGFP in the fat body. These findings suggest that the silkworm infection model with eGFP-expressing dermatophytes is useful for evaluating the therapeutic activity of orally administered anti-fungal agents against dermatophytes.
Highlights
Pathogenic fungi cause several infectious diseases, such as superficial cutaneous fungal infection and serious deep infection[1]
By using the silkworm infection model as a second screening tool after an initial in vitro screening, we recently discovered a novel antibiotic from soil bacteria, lysocin E, that is therapeutically effective in a mouse model of systemic Staphylococcus aureus infection[10]
Previous studies of silkworm infection models of C. albicans, C. glabrata, C. tropicalis, C. neoformans, and Aspergillus fumigatus demonstrated that rearing temperatures after fungal injection profoundly affect the results[29]
Summary
Pathogenic fungi cause several infectious diseases, such as superficial cutaneous fungal infection and serious deep infection[1]. Evaluation of therapeutic effects in animal models is necessary for the development of clinically effective anti-fungal agents. Mammalian animals such as the guinea pig are often used as fungal skin infection models[8]. Silkworm systemic infection models of five fungal species, Candida albicans, C. tropicalis, C. glabrata, Cryptococcus neoformans, and Aspergillus fumigatus, have been established[13,18,19,20,21] These silkworm infection models can be used to quantitatively evaluate the therapeutic efficacy of anti-fungals. Using a silkworm infection model with the filamentous fungus Aspergillus fumigatus, we discovered ASP2397, a compound that has therapeutic effects in a mouse infection model[20] This finding suggests that silkworms are useful for identifying novel anti-fungal drugs. To evaluate anti-fungal drugs against dermatophytes, we aimed to establish a novel silkworm infection model
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