Metals at the Host–Fungal Pathogen Battleground Original paper
Researched by:
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Karen Pendergrass
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Karen Pendergrass
Karen 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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Metals
Metals
OverviewHeavy metals play a significant and multifaceted role in the pathogenicity of microbial species. Their involvement can be viewed from two primary perspectives: the toxicity of heavy metals to microbes and the exploitation of heavy metals by microbial pathogens to establish infections and evade the host immune response. Understanding these aspects is critical for both […]
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Karen Pendergrass
Researched by:
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Karen Pendergrass
ID
Karen Pendergrass
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 reviewed?
This review, titled “Metals at the Host–Fungal Pathogen Battleground” by Garg et al. (2024), provides a comprehensive analysis of how fungal pathogens and their mammalian hosts engage in a dynamic, metal-centric battle during infection. The paper focuses on four key transition metals—iron (Fe), copper (Cu), zinc (Zn), and manganese (Mn)—and discusses their dual roles as essential micronutrients and toxic agents. The review examines how the host immune system manipulates metal availability to control fungal infections through nutritional immunity and metal toxicity, and how fungi adapt through sophisticated metal uptake, detoxification, and cofactor-utilization systems.
Who was reviewed?
The review explores fungal pathogens of major clinical concern, primarily Candida albicans, Cryptococcus neoformans, Aspergillus fumigatus, Histoplasma capsulatum, and other pathogenic molds and yeasts. It includes insights drawn from model organisms such as Saccharomyces cerevisiae while highlighting evolutionary expansions in metal acquisition strategies among fungal pathogens. These fungi were examined in the context of their interaction with host immune responses and fluctuating tissue-specific metal availabilities during infection.
What were the most important findings?
One of the central insights is the host’s use of “nutritional immunity” to manipulate metal availability—either sequestering metals to starve the fungus or flooding them with toxic concentrations. Calprotectin, a neutrophil-derived metal-binding protein, plays a critical role by sequestering Zn and Mn at infection sites. During C. albicans infection, Zn and Cu levels in kidney tissue follow a biphasic pattern: an initial deprivation phase followed by toxic overload, compelling the fungus to recalibrate metal acquisition and detoxification systems. The review details distinct fungal responses to each metal: siderophore-mediated Fe acquisition, Cu detoxification through P-type ATPases and metallothioneins, Zn scavenging via zincophores like PRA1, and Mn uptake through NRAMP transporters (e.g., SMF12, SMF13). These responses are tightly regulated by metal-specific transcription factors—SEF1 and HAP for Fe, MAC1 and ACE for Cu, ZAP1 for Zn—but notably, no Mn-specific regulon has been identified, suggesting post-transcriptional regulation may dominate Mn homeostasis.
From a microbiome perspective, these findings highlight that major fungal pathogens exhibit clear dependencies on metal-acquisition genes and metalloregulation systems, suggesting that transitions in microbial metal use may be a distinguishing trait in dysbiotic or pathogenic microbiomes. The expression of zincophores and siderophore transporters, as well as evidence of calprotectin-induced nutrient metal depletion, could serve as microbial signature markers (MMAs) for fungal overgrowth and metal imbalance in tissue-specific microbiomes. Additionally, the review underscores that host micronutrient modulation—especially Fe and Mn dynamics—has significant implications for microbiome resilience and therapeutic outcomes, especially in patients receiving iron supplements or experiencing metal dysregulation from comorbidities.
What are the greatest implications of this review?
This review fundamentally shifts the framing of antifungal strategies by revealing that metals are both nutrient targets and weapons in host-pathogen interactions. For clinicians, this offers novel therapeutic opportunities: metal chelation, metallophore inhibition, and interference with fungal metal transporters could be developed into antifungal interventions. Importantly, these approaches must be designed to minimize collateral damage to commensal microbial taxa, many of which share metal acquisition strategies. The review also emphasizes that rising antifungal resistance demands novel targets, and metal-based pathways offer promising, underexploited avenues for drug development. For microbiome researchers, this paper underscores the need to integrate metallomic profiling into microbiome signatures, especially for fungal overgrowth conditions like candidiasis, aspergillosis, and histoplasmosis. Incorporating fungal metallophore gene presence, metal uptake transporters, and responses to host nutritional immunity into microbiome databases will enhance precision in diagnostics and intervention selection.