HapX in Arthroderma benhamiae: Iron Regulation Without Virulence Loss Original paper
Researched by:
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Karen Pendergrass
ID
Karen Pendergrass
Read MoreKaren Pendergrass is a microbiome researcher specializing in microbiome-targeted interventions (MBTIs). She systematically analyzes scientific literature to identify microbial patterns, develop hypotheses, and validate interventions. As the founder of the Microbiome Signatures Database, she bridges microbiome research with clinical practice. In 2012, based on her own investigative research, she became the first documented case of FMT for Celiac Disease—four years before the first published case study.
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Microbes
Microbes
Microbes, short for microorganisms, are tiny living organisms that are ubiquitous in the environment, including on and inside the human body. They play a crucial role in human health and disease, functioning within complex ecosystems in various parts of the body, such as the skin, mouth, gut, and respiratory tract. The human microbiome, which is […]
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Microbial Metallomics
Microbial Metallomics
Microbial Metallomics is the study of how microorganisms interact with metal ions in biological systems, particularly within the human microbiome.
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Karen Pendergrass
Read More
Researched by:
-
Karen Pendergrass
ID
Karen Pendergrass
Read More
Microbiome Signatures identifies and validates condition-specific microbiome shifts and interventions to accelerate clinical translation. Our multidisciplinary team supports clinicians, researchers, and innovators in turning microbiome science into actionable medicine.
Karen Pendergrass
What was studied?
This study investigated the role of the transcription factor HapX in the regulation of iron homeostasis in the pathogenic dermatophyte Arthroderma benhamiae, with particular attention to whether HapX is essential for virulence. HapX is a known regulator of fungal iron metabolism in other ascomycetes, acting through its dual role in iron acquisition during starvation and iron detoxification during excess. The authors constructed ΔhapX mutants and reconstituted strains to analyze growth phenotypes under varying iron conditions, siderophore production, and gene expression patterns of iron-regulatory pathways. Additionally, they tested virulence potential on keratinized substrates, including human hair and nails.
Who was studied?
The experiments were performed using a wild-type A. benhamiae strain (LAU2354-2), two ΔhapX deletion mutants, and their respective gene-reconstituted strains (hapX^C). Growth, siderophore production, and gene expression were evaluated under iron-replete and iron-starved conditions, including exposure to deferoxamine (a xenosiderophore). Virulence was assessed via in vitro growth assays on human keratin substrates.
Most important findings
HapX is essential for iron homeostasis in Arthroderma benhamiae, governing adaptation to both iron limitation and excess. Deletion of the hapX gene (ΔhapX) resulted in impaired fungal growth, reduced conidiation, and decreased biomass under iron-starved conditions or in the presence of the iron chelator deferoxamine. The mutants also exhibited a distinct reddish hyphal pigmentation, likely due to accumulation of heme precursors. Molecular analyses revealed downregulation of siderophore biosynthetic genes sidA and sidC, along with reduced secretion of the extracellular siderophore ferrichrome C, though intracellular ferricrocin levels remained unaffected. Additionally, HapX-deficient strains failed to repress iron-consuming genes (cccA, hemA, cycA, lysF) during iron deprivation, underscoring its role in balancing iron usage. The ΔhapX strains were also hypersensitive to iron overload, showing growth inhibition at ≥5 mM FeSO₄, implicating HapX in iron detoxification pathways. Despite these metabolic disruptions, virulence remained intact on keratin-rich substrates like hair and nails, suggesting that keratin may supply bioavailable iron or that alternative acquisition systems, such as reductive iron assimilation, can compensate for the loss of HapX-regulated siderophore function.
| Functional Role | ΔhapX Phenotype |
|---|---|
| Iron Starvation Response | ↓ sidA, sidC transcription; ↓ ferrichrome C |
| Iron Detoxification | ↑ sensitivity to FeSO₄; ↓ cccA induction |
| Gene Regulation | ↑ hemA, lysF, cycA, sreA in iron-starved state |
| Virulence on Keratin | No impairment in hair/nail substrate infection |
Key implications
While HapX is central to iron regulation in A. benhamiae, it is not required for keratin substrate colonization, suggesting that dermatophyte virulence mechanisms are adapted to relatively iron-rich or accessible environments like skin, nails, and hair. This divergence from pathogens such as Aspergillus fumigatus or Candida albicans, where HapX is critical for virulence, highlights the need for pathogen-specific strategies when targeting iron acquisition therapeutically. Furthermore, the redundancy of HapX in virulence points toward alternative iron uptake systems such as reductive iron assimilation or low-affinity transporters in dermatophytes. These compensatory pathways represent potential antifungal targets.