Abstract
While fatty acids are known to be toxic to dermatophytes, key physiological aspects of the Trichophyton rubrum response to undecanoic acid (UDA), a medium chain saturated fatty acid (C11:0), are not well understood. Thus, we analysed RNA-seq data from T. rubrum exposed to sub-lethal doses of UDA for 3 and 12 h. Three putative pathways were primarily involved in UDA detoxification: lipid metabolism and cellular membrane composition, oxidative stress, and pathogenesis. Biochemical assays showed cell membrane impairment, reductions in ergosterol content, and an increase in keratinolytic activity following UDA exposure. Moreover, we assessed differential exon usage and intron retention following UDA exposure. A key enzyme supplying guanine nucleotides to cells, inosine monophosphate dehydrogenase (IMPDH), showed high levels of intron 2 retention. Additionally, phosphoglucomutase (PGM), which is involved in the glycogen synthesis and degradation as well as cell wall biosynthesis, exhibited a significant difference in exon 4 usage following UDA exposure. Owing to the roles of these enzymes in fungal cells, both have emerged as promising antifungal targets. We showed that intron 2 retention in impdh and exon 4 skipping in pgm might be related to an adaptive strategy to combat fatty acid toxicity. Thus, the general effect of UDA fungal toxicity involves changes to fungal metabolism and mechanisms for regulating pre-mRNA processing events.
Highlights
Dermatophytes are filamentous fungi that are able to infect keratinized tissues, such as the nails, hair, and skin[1]
Undecanoic acid (UDA) exposure is assumed to lead to a breakdown in phospholipid synthesis, which in turn cause changes in membrane composition, promoting membrane damage and partial growth inhibition[25]
Our data revealed new insights into the mechanisms with which T. rubrum attempts to overcome UDA exposure, showing three main categories of genes affected by UDA: lipid metabolism and cellular membrane composition, oxidative stress, and pathogenesis with a focus on protease secretion
Summary
Dermatophytes are filamentous fungi that are able to infect keratinized tissues, such as the nails, hair, and skin[1] They are highly pathogenic, causing most cases of superficial mycosis worldwide[2,3]. Several cases of resistance to antifungals have been reported, indicating a need to identify new therapeutic targets and new antifungal drugs[7] In this context, the antimycotic activity of fatty acids has long been known. Dermatophyte–host interactions trigger the transcription of genes that allow for the adherence and penetration of the pathogen into the host tissue, enabling it to scavenge nutrients and overcome host defence mechanisms This genetic adaptive machinery leads to cell wall remodelling and the secretion of a battery of endo- and exoproteases that degrade keratinized structures, using them as nutrients[15,16,17]. The data generated provide evidence that UDA induces AS of several genes involved in diverse metabolic pathways
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