Essential metals at the host-pathogen interface: nutritional immunity and micronutrient assimilation by human fungal pathogens

Crawford, Aaron; Wilson, Duncan

doi:10.1093/femsyr/fov071

Cited by 94 publications

(81 citation statements)

References 95 publications

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“…Of particular interest was our finding of the robust interaction between carriage with manganese and copper. Copper is a required nutrient for C. albicans (serving as a cofactor for C. albicans SODs which protect cells from oxidative stress [26]) and also has inherent antifungal and antimicrobial activity by participating in Fenton reactions to generate harmful reactive oxygen species [38,39]. Moreover, Histatin 5 binds copper with high affinity, and this increases the killing activity of the peptide [40].…”

Section: Discussionmentioning

confidence: 99%

“…Although manganese, different from many transition metals, is not prone to Fenton reactions [41], it is important for the function of antioxidant SOD proteins in C. albicans , particularly when copper is unavailable [26]. Reciprocally, in the oral environment, calprotectin sequesters manganese as the mechanism of its antimicrobial activity [39]. Thus, there are several possible mechanisms by which copper and manganese modulate Candida in the oral environment.…”

Section: Discussionmentioning

confidence: 99%

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Salivary metals, age, and gender correlate with cultivable oral Candida carriage levels

Norris

Friedman

Chen

et al. 2018

Journal of Oral Microbiology

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Background: Little is known about the normal range of metal levels in unstimulated saliva, nor whether these might impact Candida carriage in healthy individuals. Both are important in determining which populations are at risk for candidiasis, as the availability of metal ions can influence the growth and pathogenesis of Candida albicans. Objective: We quantified salivary metals of healthy individuals to determine the correlation with C. albicans oral colonization. Design: Unstimulated whole saliva was collected from healthy adults and plated to determine fungal carriage, and metal content was measured using ICP-mass spectrometry (ICP-MS). Results: Zinc was most abundant, followed by iron, copper, manganese, and nickel. Cultivable oral Candida carriage was found in 48% of people. Total protein levels did not differ in salivas from donors with or without carriage. However, innate fungicidal activity was increased in donors with carriage; correlations between levels of several metals were stronger in salivas with fungal carriage, indicating a shift in the oral environment. Concentrations of copper and manganese, as well as age and gender, were significantly predictive of carriage levels in a multiple regression model. Conclusions: Salivary copper and manganese content along with age and gender could be used as a predictive metric for individuals that are more susceptible to Candida overgrowth.

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Section: Discussionmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

Salivary metals, age, and gender correlate with cultivable oral Candida carriage levels

Norris

Friedman

Chen

et al. 2018

Journal of Oral Microbiology

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“…C. albicans and other pathogenic microbes must acquire these metals from the host, and as part of the innate immune response, the host attempts to limit metal availability through a process known as nutritional immunity (2)(3)(4)(5). However, transition metals are also potentially toxic to microbes, and with Zn and Cu there is increasing evidence that the host also exploits toxic levels of these metals in its antimicrobial weaponry (2,6).…”

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confidence: 99%

Role of Calprotectin in Withholding Zinc and Copper from Candida albicans

et al. 2018

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The opportunistic fungal pathogen Candida albicans acquires essential metals from the host, yet the host can sequester these micronutrients through a process known as nutritional immunity. How the host withholds metals from C. albicans has been poorly understood; here we examine the role of calprotectin (CP), a transition metal binding protein. When CP depletes bioavailable Zn from the extracellular environment, C. albicans strongly upregulates ZRT1 and PRA1 for Zn import and maintains constant intracellular Zn through numerous cell divisions. We show for the first time that CP can also sequester Cu by binding Cu(II) with subpicomolar affinity. CP blocks fungal acquisition of Cu from serum and induces a Cu starvation stress response involving SOD1 and SOD3 superoxide dismutases. These transcriptional changes are mirrored when C. albicans invades kidneys in a mouse model of disseminated candidiasis, although the responses to Cu and Zn limitations are temporally distinct. The Cu response progresses throughout 72 h, while the Zn response is short-lived. Notably, these stress responses were attenuated in CP null mice, but only at initial stages of infection. Thus, Zn and Cu pools are dynamic at the hostpathogen interface and CP acts early in infection to restrict metal nutrients from C. albicans.

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“…Therefore, future anti-C. albicans therapies may also include the reconstruction of physiologically relevant pH values and CO 2 concentrations at the sites of infections to prevent or at least hinder the spread of Candida cells toward deeper tissues. Another therapeutic approach may rely on the disturbance of the hemoglobin and hemin uptake by C. albicans through hemoglobin/heme-binding receptors on the surface of Candida cells [32,70,71], which may also reduce the virulence of C. albicans [33]. It is worth noting that the dimorphic morphological transitions of C. albicans is an extensive studied area in fungal biology and are considered as promising targets in future antifungal drug research [72].…”

Section: Discussionmentioning

confidence: 99%

Effects of hemin, CO2, and pH on the branching of Candida albicans filamentous forms

Jakab

Antal

Emri

et al. 2016

Acta Microbiologica et Immunologica Hungarica

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Morphological transitions of wild-type and oxidative stress-tolerant Candida albicans strains were followed in the RPMI-FBS culture medium at pH values and CO 2 levels characteristic for the anatomical niches inhabited by this opportunistic human pathogen fungus, including the oral cavity as well as the intestinal and vaginal lumens. Selected cultures were also supplemented with hemin modeling bleedings. Germination as well as elongation and branching of hyphae were monitored in the cultures using time-lapse video microscopy. Unexpectedly, branching time, which is defined as the time taken until the first branch of hypha emerges for the first time after germination, correlated well with alterations in the environmental conditions meanwhile no such correlations were found for germination time (time lasted until the *Corresponding author; E-mail: pocsi.istvan@science.unideb.hu : 10.1556/030.63.2016.023 First published online December 8, 2016 1217-8950/$ 20.00 © 2016 Akadémiai Kiadó, Budapest appearance of the germination tube). Based on these observations, hypotheses were set up to estimate the significance of branching time in the pathogenesis of both superficial and systemic candidiases.Acta Microbiologica et Immunologica Hungarica 63 (4), pp. 387-403 (2016) DOI

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Essential metals at the host-pathogen interface: nutritional immunity and micronutrient assimilation by human fungal pathogens

Cited by 94 publications

References 95 publications

Salivary metals, age, and gender correlate with cultivable oral Candida carriage levels

Salivary metals, age, and gender correlate with cultivable oral Candida carriage levels

Role of Calprotectin in Withholding Zinc and Copper from Candida albicans

Effects of hemin, CO2, and pH on the branching of Candida albicans filamentous forms

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