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

Hu, Guanggan; Caza, Mélissa; Cadieux, Brigitte; Chan, Vivienne; Liu, Victor; Kronstad, James W.

doi:10.1128/iai.01037-12

Cited by 73 publications

(127 citation statements)

References 75 publications

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“…In this study, we demonstrated a previously unknown function of flippases in physiological and pathogenic secretion-related events used by C. neoformans. To the best of our knowledge, cryptococcal regulators of secretion described so far include the products of the SEC (51,58,64) and CAP genes (65-70), Golgi reassembly and stacking protein (30), protein kinase A (71), vacuolar Ca 2ϩ transporters (35,59), and the vacuolar protein Vps23 (72). Mutants with altered expression of the genes coding for each of these secretory regulators are hypovirulent or avirulent in mice.…”

Section: Discussionmentioning

confidence: 99%

Role of the Apt1 Protein in Polysaccharide Secretion by Cryptococcus neoformans

et al. 2014

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e Flippases are key regulators of membrane asymmetry and secretory mechanisms. Vesicular polysaccharide secretion is essential for the pathogenic mechanisms of Cryptococcus neoformans. On the basis of the observations that flippases are required for polysaccharide secretion in plants and the putative Apt1 flippase is required for cryptococcal virulence, we analyzed the role of this enzyme in polysaccharide release by C. neoformans, using a previously characterized apt1⌬ mutant. Mutant and wild-type (WT) cells shared important phenotypic characteristics, including capsule morphology and dimensions, glucuronoxylomannan (GXM) composition, molecular size, and serological properties. The apt1⌬ mutant, however, produced extracellular vesicles (EVs) with a lower GXM content and different size distribution in comparison with those of WT cells. Our data also suggested a defective intracellular GXM synthesis in mutant cells, in addition to changes in the architecture of the Golgi apparatus. These findings were correlated with diminished GXM production during in vitro growth, macrophage infection, and lung colonization. This phenotype was associated with decreased survival of the mutant in the lungs of infected mice, reduced induction of interleukin-6 (IL-6) cytokine levels, and inefficacy in colonization of the brain. Taken together, our results indicate that the lack of APT1 caused defects in both GXM synthesis and vesicular export to the extracellular milieu by C. neoformans via processes that are apparently related to the pathogenic mechanisms used by this fungus during animal infection.

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Section: Discussionmentioning

confidence: 99%

Role of the Apt1 Protein in Polysaccharide Secretion by Cryptococcus neoformans

et al. 2014

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“…5C). This insertion mutant was obtained in a previously reported screen for mutants with reduced growth on hemin, and it had a more obvious growth defect than with the fre2⌬ strain (35). Interestingly, the fre2 insertion mutant was generated in the background of a cfo1⌬ mutant that lacks the ferroxidase of the high-affinity iron uptake system (35).…”

Section: Ferric and Cupric Reductase Activities Of Fre Deletion Strainsmentioning

confidence: 99%

“…This insertion mutant was obtained in a previously reported screen for mutants with reduced growth on hemin, and it had a more obvious growth defect than with the fre2⌬ strain (35). Interestingly, the fre2 insertion mutant was generated in the background of a cfo1⌬ mutant that lacks the ferroxidase of the high-affinity iron uptake system (35). Thus, the difference in the growth defects between the fre2 T-DNA insertion and deletion mutants indicates that the high-affinity iron uptake system, along with Fre2, makes a contribution to iron acquisition from hemin.…”

Section: Ferric and Cupric Reductase Activities Of Fre Deletion Strainsmentioning

confidence: 99%

Role of Ferric Reductases in Iron Acquisition and Virulence in the Fungal Pathogen Cryptococcus neoformans

Saikia

Oliveira

et al. 2014

Infect Immun

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Iron acquisition is critical for the ability of the pathogenic yeast Cryptococcus neoformans to cause disease in vertebrate hosts. In particular, iron overload exacerbates cryptococcal disease in an animal model, defects in iron acquisition attenuate virulence, and iron availability influences the expression of major virulence factors. C. neoformans acquires iron by multiple mechanisms, including a ferroxidase-permease high-affinity system, siderophore uptake, and utilization of both heme and transferrin. In this study, we examined the expression of eight candidate ferric reductase genes and their contributions to iron acquisition as well as to ferric and cupric reductase activities. We found that loss of the FRE4 gene resulted in a defect in production of the virulence factor melanin and increased susceptibility to azole antifungal drugs. In addition, the FRE2 gene was important for growth on the iron sources heme and transferrin, which are relevant for proliferation in the host. Fre2 may participate with the ferroxidase Cfo1 of the high-affinity uptake system for growth on heme, because a mutant lacking both genes showed a more pronounced growth defect than the fre2 single mutant. A role for Fre2 in iron acquisition is consistent with the attenuation of virulence observed for the fre2 mutant. This mutant also was defective in accumulation in the brains of infected mice, a phenotype previously observed for mutants with defects in high-affinity iron uptake (e.g., the cfo1 mutant). Overall, this study provides a more detailed view of the iron acquisition components required for C. neoformans to cause cryptococcosis.

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“…Interestingly, Vps23 has been shown to be involved in iron acquisition, capsule formation, and virulence. However, these functions may be explained by the role of Vps23 in endocytosis, and its contribution, like other ESCRT factors, in Rim101 processing in C. neoformans has not been demonstrated yet (106). Many of the genes involved in cell wall biosynthesis and remodeling are regulated by Rim101 in C. neoformans (CHS4, CHS5, CHS6, CHS8, SKN1, FKS1, KRE6, CDA3, CHI22, and AGS1) (107).…”

Section: Ph Signaling and Cryptococcus Neoformans Virulencementioning

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

Cited by 73 publications

References 75 publications

Role of the Apt1 Protein in Polysaccharide Secretion by Cryptococcus neoformans

Role of the Apt1 Protein in Polysaccharide Secretion by Cryptococcus neoformans

Role of Ferric Reductases in Iron Acquisition and Virulence in the Fungal Pathogen Cryptococcus neoformans

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

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