Fungal infections are a serious global concern because of their ability to spread and colonize host tissues in immunocompromised individuals. Such infections have been frequently reported worldwide and are currently gaining clinical research relevance owing to their resistant character, representing a bottleneck in treating affected people. Resistant fungi are an emergent public health threat. The upsurge of such pathogens has led to new research toward unraveling the destructive potential evoked by these species. Some fungi—grouped into Candida, Aspergillus, and Cryptococcus—are causative agents of severe and systemic infections. They are associated with high mortality rates and have recently been described as sources of coinfection in COVID-hospitalized patients. Despite the efforts to elucidate the challenges of colonization, dissemination, and infection severity, the immunopathogenesis of fungal diseases remains a pivotal characteristic in fungal burden elimination. The struggle between the host immune system and the physiological strategies of the fungi to maintain cellular viability is complex. In this brief review, we highlight the relevance of drug resistance phenotypes in fungi of clinical significance, taking into consideration their physiopathology and how the scientific community could orchestrate their efforts to avoid fungal infection dissemination and deaths.

Trichophyton rubrum is the primary causative agent of dermatophytosis worldwide. This fungus colonizes keratinized tissues and uses keratin as a nutritional source during infection. In T. rubrum–host interactions, sensing a hostile environment triggers the adaptation of its metabolic machinery to ensure its survival. The glyoxylate cycle has emerged as an alternative metabolic pathway when glucose availability is limited; this enables the conversion of simple carbon compounds into glucose via gluconeogenesis. In this study, we investigated the impact of stuA deletion on the response of glyoxylate cycle enzymes during fungal growth under varying culture conditions in conjunction with post-transcriptional regulation through alternative splicing of the genes encoding these enzymes. We revealed that the ΔstuA mutant downregulated the malate synthase and isocitrate lyase genes in a keratin-containing medium or when co-cultured with human keratinocytes. Alternative splicing of an isocitrate lyase gene yielded a new isoform. Enzymatic activity assays showed specific instances where isocitrate lyase and malate synthase activities were affected in the mutant strain compared to the wild type strain. Taken together, our results indicate a relevant balance in transcriptional regulation that has distinct effects on the enzymatic activities of malate synthase and isocitrate lyase.

Fungi can remarkably sense and adapt to various extracellular stimuli and stress conditions. Oxidative stress, which results from an imbalance between reactive oxygen species production and antioxidant defenses, leads to cellular damage and death. In Trichophyton rubrum, oxidative stress is managed by a complex antioxidant system, including thioredoxins, glutathione, catalases, peroxidases, and superoxide dismutase, with glutathione playing a crucial role. The fungus also responds to oxidative stress through critical pathways such as the glycerol high-osmolarity pathway, activator protein 1 transcription factor, and responsive regulator SKN7. To better understand the role of the transcription factor StuA in regulating oxidative stress-related genes within these pathways, we conducted gene expression studies in ΔstuA mutant and wild-type strains of T. rubrum cultivated in keratin and under oxidative stress induced by hydrogen peroxide. Our results revealed significant downregulation of essential antioxidant genes, including glutathione transferases and catalases, in the ΔstuA mutant. Moreover, catalase and glutathione S-transferase activities were impaired in the mutants under stress conditions, highlighting the impact of this mutation. These findings underscore the critical role of StuA in the oxidative stress response and fungal pathogenesis and provide new insights into T. rubrum’s adaptive mechanisms.

Trichophyton rubrum is the leading causative agent of dermatophytosis worldwide. Keratinocytes are the first line of defense that drives an immune response against fungal invasion. Host-specific pattern recognition receptors (PRRs) recognize pathogen-associated molecular patterns (PAMPs) to trigger immunological pathways. Fungal cell wall components are the primary sources of fungal PAMPs, and some pathogens increase cell wall rearrangement to evade the immune system. Glycolysis and enhanced lactate levels are critical for improving host immune responses to fungal infections. Using reverse transcription–quantitative polymerase chain reaction (RT-qPCR), we evaluated the transcriptional responses of human genes involved in fungal recognition and glycolytic metabolism and fungal cell-wall-related genes in a co-culture model of human keratinocytes with T. rubrum. We observed the upregulation of several Toll-like receptors (TLRs), NOD-like receptors (NLRs), and glycolytic genes. Complementarily, we measured intra- and extracellular glucose levels and the increase in lactate production in the co-culture supernatant. We noted a distinct transcriptional regulation pattern of fungal cell-wall-related genes from fungal growth on keratin as the primary carbon source compared to co-culture with human keratinocytes. Our results showed new insights into the transcriptional adaptation of keratinocytes, particularly in regulating genes involved in sensing and metabolic processes, during the interaction with T. rubrum.

Background: Trichoderma reesei is the main filamentous fungus used in industry to produce cellulases. Over the last decades, there have been a strong increase in the understanding of the regulatory network controlling cellulase-coding gene expression in response to a number of inducers and environmental signals. In this sense, the role of calcium and the Calcineurin-responsive protein (CRZ1) has been investigated in industrially relevant strains of T. reesei RUT-C30, but this system has not been investigated in wild-type reference strain of this fungus. Results: Here, we investigated the role of CRZ1 and Ca ²⁺ signaling in the fungus T. reesei QM6a. For this, we first searched for potential CRZ1 binding sites in promoter regions of key genes coding holocellulases, as well as transcriptional regulators and sugar and calcium transporters. Using a nearly constructed T. reesei Δ crzl strain, we demonstrated that most of the genes expected to be regulated by CRZ1 were affected in the mutant strain induced with sugarcane bagasse (SCB) and cellulose. In particular, our data demonstrate that Ca ²⁺ acts synergistically with CRZ1 to modulate gene expression, but also exerts CRZ1-independent regulatory role in gene expression in T. reesei , suggesting the existence of additional Ca ²⁺ sensing mechanisms in this fungus. Conclusions: This work presents new evidence on the regulatory role of CRZ1 and Ca ²⁺ sensing in the regulation of cellulolytic enzymes in T. reesei , evidencing significant and previously unknown function of this Ca ²⁺ sensing system in the control key transcriptional regulators (XYR1 and CRE1) and on the expression of genes related to sugar and Ca ²⁺ transport. Taken together, the data obtained here provide new evidence on the regulatory network of T. reesei related to plant biomass deconstruction.

Fungi can remarkably sense and adapt to various extracellular stimuli and stress conditions. Oxidative stress, which results from an imbalance between reactive oxygen species production and antioxidant defenses, leads to cellular damage and death. In Trichophyton rubrum, oxidative stress is managed by a complex antioxidant system including thioredoxins, glutathione, catalases, peroxidases, and superoxide dismutase, with glutathione playing a crucial role. The fungus also responds to oxidative stress through critical pathways such as the glycerol high osmolarity pathway, activator protein 1 transcription factor, and responsive regulator SKN7. To better understand the role of the transcription factor StuA in regulating oxidative stress-related genes within these pathways, we conducted gene expression studies in ΔstuA mutant and wild-type strains of T. rubrum cultivated in keratin and under oxidative stress induced by hydrogen peroxide. Our results revealed significant downregulation of essential antioxidant genes, including glutathione transferases and catalases, in the ΔstuA mutant. Moreover, catalase and glutathione S-transferase activities were impaired in the mutants under stress conditions, highlighting the impact of this mutation. These findings underscore the critical role of StuA in the oxidative stress response and fungal pathogenesis and provide new insights into T. rubrum's adaptive mechanisms.