Iron and fungal pathogenesis: a case study with Cryptococcus neoformans

Jung, Won Hee; Kronstad, James W.

doi:10.1111/j.1462-5822.2007.01077.x

Cited by 99 publications

(112 citation statements)

References 57 publications

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“…Several recent studies have shown that fungal nutrient and element acquisition pathways may be critical for pathogenicity of both plant and human pathogens [40,41]. For example, all living organisms utilize Cu as cofactor of enzymes functioning in many cellular biochemical processes [3].…”

Section: Discussionmentioning

confidence: 99%

Contribution of ATPase copper transporters in animal but not plant virulence of the crossover pathogen Aspergillus flavus

et al. 2018

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The ubiquitous fungus Aspergillus flavus is notorious for contaminating many important crops and food-stuffs with the carcinogenic mycotoxin, aflatoxin. This fungus is also the second most frequent Aspergillus pathogen after A. fumigatus infecting immunosuppressed patients. In many human fungal pathogens including A. fumigatus, the ability to defend from toxic levels of copper (Cu) is essential in pathogenesis. In A. fumigatus, the Cu-fist DNA binding protein, AceA, and the Cu ATPase transporter, CrpA, play critical roles in Cu defense. Here, we show that A. flavus tolerates higher concentrations of Cu than A. fumigatus and other Aspergillus spp. associated with the presence of two homologs of A. fumigatus CrpA termed CrpA and CrpB. Both crpA and crpB are transcriptionally induced by increasing Cu concentrations via AceA activity. Deletion of crpA or crpB alone did not alter high Cu tolerance, suggesting they are redundant. Deletion of both genes resulted in extreme Cu sensitivity that was greater than that following deletion of the regulatory transcription factor aceA. The ΔcrpAΔcrpB and ΔaceA strains were also sensitive to ROI stress. Compared to wild type, these mutants were impaired in the ability to colonize maize seed treated with Cu fungicide but showed no difference in virulence on non-treated seed. A mouse model of invasive aspergillosis showed ΔcrpAΔcrpB and to a lesser degree ΔaceA to be significantly reduced in virulence, following the greater sensitivity of ΔcrpAΔcrpB to Cu than ΔaceA.

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Section: Discussionmentioning

confidence: 99%

Contribution of ATPase copper transporters in animal but not plant virulence of the crossover pathogen Aspergillus flavus

et al. 2018

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“…Iron availability influences at least two major virulence traits in this fungus, including the production of a polysaccharide capsule and deposition of melanin in the cell wall (2,3,4,5,6). Additionally, iron overload exacerbates cryptococcal disease in a mouse model of cryptococcosis (7).…”

mentioning

confidence: 99%

“…neoformans has multiple acquisition mechanisms to obtain iron, including a high-affinity uptake system composed of the iron permease Cft1 and the ferroxidase Cfo1, a siderophore uptake pathway, cell surface reductases, and exported reductants such as 3-hydroxyanthranilic acid; in addition, melanin in the cell wall may contribute to ferric iron reduction (3,8,9). The Cft1/Cfo1 permease/ferroxidase complex is essential for reductive iron uptake, for iron acquisition from transferrin, and for full virulence in a mouse model of cryptococcosis (10,11).…”

mentioning

confidence: 99%

Cryptococcus neoformans Requires the ESCRT Protein Vps23 for Iron Acquisition from Heme, for Capsule Formation, and for Virulence

et al. 2013

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Iron availability is a key regulator of virulence factor elaboration in Cryptococcus neoformans, the causative agent of fungal meningoencephalitis in HIV/AIDS patients. In addition, iron is an essential nutrient for pathogen proliferation in mammalian hosts but little is known about the mechanisms of iron sensing and uptake in fungal pathogens that attack humans. In this study, we mutagenized C. neoformans by Agrobacterium-mediated T-DNA insertion and screened for mutants with reduced growth on heme as the sole iron source. Among 34 mutants, we identified a subset with insertions in the gene for the ESCRT-I (endosomal sorting complex required for transport) protein Vps23 that resulted in a growth defect on heme, presumably due to a defect in uptake via endocytosis or misregulation of iron acquisition from heme. Remarkably, vps23 mutants were also defective in the elaboration of the cell-associated capsular polysaccharide that is a major virulence factor, while overexpression of Vps23 resulted in cells with a slightly enlarged capsule. These phenotypes were mirrored by a virulence defect in the vps23 mutant in a mouse model of cryptococcosis and by hypervirulence of the overexpression strain. Overall, these results reveal an important role for trafficking via ESCRT functions in both heme uptake and capsule formation, and they further reinforce the connection between iron and virulence factor deployment in C. neoformans.

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“…One of the principal Rim101-dependent responses to alkaline conditions involves adaptation to iron starvation. Tolerance of iron deprivation at physiological pH is one of the most important virulence determinants of fungi, as freely available iron is strongly limited in human hosts, protecting the host against microorganisms unable to increase iron uptake (7,52,68,(74)(75)(76)(77)(78). Transcriptional analyses have identified several genes involved in iron metabolism and transport, including some Rim101-dependent targets, such as the siderophore iron transporter genes ARN1 and FET3 and the ferric reductase and ion permease genes ENA1, RBT2, FRE2, FRE5, FRE8, FRP1, FRP2, CTR1, and ZRT1 (52,74,79).…”

Section: Pacc/rim101 Effectors and Downstream Targets Involved In Patmentioning

confidence: 99%

pH Signaling in Human Fungal Pathogens: a New Target for Antifungal Strategies

Cornet

Gaillardin

2014

Eukaryot Cell

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dFungi are exposed to broadly fluctuating environmental conditions, to which adaptation is crucial for their survival. An ability to respond to a wide pH range, in particular, allows them to cope with rapid changes in their extracellular settings. PacC/Rim signaling elicits the primary pH response in both model and pathogenic fungi and has been studied in multiple fungal species. In the predominant human pathogenic fungi, namely, Candida albicans, Aspergillus fumigatus, and Cryptococcus neoformans, this pathway is required for many functions associated with pathogenesis and virulence. Aspects of this pathway are fungus specific and do not exist in mammalian cells. In this review, we highlight recent advances in our understanding of PacC/Rim-mediated functions and discuss the growing interest in this cascade and its factors as potential drug targets for antifungal strategies. We focus on both conserved and distinctive features in model and pathogenic fungi, highlighting the specificities of PacC/Rim signaling in C. albicans, A. fumigatus, and C. neoformans. We consider the role of this pathway in fungal virulence, including modulation of the host immune response. Finally, as now recognized for other signaling cascades, we highlight the role of pH in adaptation to antifungal drug pressure. By acting on the PacC/Rim pathway, it may therefore be possible (i) to ensure fungal specificity and to limit the side effects of drugs, (ii) to ensure broad-spectrum efficacy, (iii) to attenuate fungal virulence, (iv) to obtain additive or synergistic effects with existing antifungal drugs through tolerance inhibition, and (v) to slow the emergence of resistant mutants.

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Iron and fungal pathogenesis: a case study with Cryptococcus neoformans

Cited by 99 publications

References 57 publications

Contribution of ATPase copper transporters in animal but not plant virulence of the crossover pathogen Aspergillus flavus

Contribution of ATPase copper transporters in animal but not plant virulence of the crossover pathogen Aspergillus flavus

Cryptococcus neoformans Requires the ESCRT Protein Vps23 for Iron Acquisition from Heme, for Capsule Formation, and for Virulence

pH Signaling in Human Fungal Pathogens: a New Target for Antifungal Strategies

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