Peeling the onion: the outer layers of Cryptococcus neoformans

Agustinho, Daniel Paiva; Miller, Liza; Li, Lucy X.; Doering, Tamara L.

doi:10.1590/0074-02760180040

Cited by 47 publications

(39 citation statements)

References 132 publications

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“…Cryptococcus neoformans cell wall is a dynamic structure that undergoes constant remodeling to modulate the distribution and crosslinking of its components necessary for cellular growth and division (Doering, 2009;Agustinho et al, 2018;Wang et al, 2018). Cryptococcus cell wall is a two-layered structure composed by α-1,3-glucan, β-1,3 and β-1,6-glucan, chitin, chitosan, mannoproteins and other GPI-anchored proteins (Baker et al, 2007;Doering, 2009;O'Meara and Alspaugh, 2012;Wang et al, 2018).…”

Section: Composition Biosynthesis and Interaction With The Hostmentioning

confidence: 99%

“…The fungal cell wall is an essential structure with great plasticity that is vital to maintaining cellular integrity and viability. The cell wall plays an important role in different biological functions such as controlling cellular permeability and protecting the cell from osmotic and mechanical stress (Ponton, 2008;Gow et al, 2017;Agustinho et al, 2018). In addition to these important functions, the cell wall mediates interactions with the external environment through adhesins and a large number of receptors that, after their activation, will trigger a complex cascade of signals inside the cell (Ponton, 2008).…”

Section: Introductionmentioning

confidence: 99%

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The Fungal Cell Wall: Candida, Cryptococcus, and Aspergillus Species

et al. 2020

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The fungal cell wall is located outside the plasma membrane and is the cell compartment that mediates all the relationships of the cell with the environment. It protects the contents of the cell, gives rigidity and defines the cellular structure. The cell wall is a skeleton with high plasticity that protects the cell from different stresses, among which osmotic changes stand out. The cell wall allows interaction with the external environment since some of its proteins are adhesins and receptors. Since, some components have a high immunogenic capacity, certain wall components can drive the host's immune response to promote fungus growth and dissemination. The cell wall is a characteristic structure of fungi and is composed mainly of glucans, chitin and glycoproteins. As the components of the fungal cell wall are not present in humans, this structure is an excellent target for antifungal therapy. In this article, we review recent data on the composition and synthesis, influence of the components of the cell wall in fungi-host interaction and the role as a target for the next generation of antifungal drugs in yeasts (Candida and Cryptococcus) and filamentous fungi (Aspergillus).

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Section: Composition Biosynthesis and Interaction With The Hostmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

The Fungal Cell Wall: Candida, Cryptococcus, and Aspergillus Species

et al. 2020

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“…The complex cell wall structure of C. neoformans protects the cell from the extracellular stressors including antifungals. A sturdier cell wall can also serve as a less permeable barrier to antifungal drugs, making them less effective (45). We found that following treatment with caspofungin wild type cells had an increase in the cell wall chitin.…”

Section: Discussionmentioning

confidence: 99%

Puf4 Mediates Post-transcriptional Regulation of Caspofungin Resistance inCryptococcus neoformans

Kalem

Subbiah

Leipheimer

et al. 2020

Preprint

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24Echinocandins have been on the market for 20 years, yet they are the newest class of 25 antifungal drugs. The human fungal pathogen Cryptococcus neoformans is intrinsically resistant 26 to the echinocandin antifungal drug caspofungin, which targets the b-1,3-glucan synthase 27 encoded by the FKS1. Analysis of a C. neoformans puf4∆ mutant, lacking the pumilio/FBF RNA 28 binding protein family member Puf4, revealed exacerbated caspofungin resistance. In contrast, 29 overexpression of PUF4 resulted in caspofungin sensitivity. The FKS1 mRNA contains three 30 Puf4-binding elements (PBEs) in its 5' untranslated region. Puf4 binds with specificity to this 31 region of the FKS1. The FKS1 mRNA was destabilized in the puf4∆ mutant, and the abundance 32 of the FKS1 mRNA was reduced compared to wild type, suggesting that Puf4 is a positive 33 regulator FKS1 mRNA stability. In addition to FKS1, the abundance of additional cell wall 34 biosynthesis genes, including chitin synthases (CHS3, CHS4, CHS6) and deacetylases (CDA1, 35 CDA2, CDA3) as well as a b-1,6-glucan synthase gene (SKN1) was regulated by Puf4 during a 36 caspofungin time course. The use of fluorescent dyes to quantify cell wall components revealed 37 that the puf4∆ mutant had increased chitin content, suggesting a cell wall composition that is 38 less reliant on b-1,3-glucan. Overall, our findings suggest a mechanism by which caspofungin 39 resistance, and more broadly, cell wall biogenesis, is regulated post-transcriptionally by Puf4. 40 41 Importance 42 Cryptococcus neoformans is an environmental fungus that causes pulmonary and central 43 nervous system infections. It is also responsible for 15% of AIDS-related deaths. A major 44 contributor to the high morbidity and mortality statistics is the lack of safe and effective 45 antifungal therapies, especially in resource-poor settings. Yet, antifungal drug development has 46 stalled in the pharmaceutical industry. Therefore, it is of importance to understand the mechanism by which C. neoformans is resistant to caspofungin in order to design adjunctive 48 therapies to potentiate its activity toward this important pathogen. 50 Introduction 51Invasive deep mycoses primarily impact immunocompromised populations causing high rates of 52 morbidity and mortality (1, 2). The pathogenic fungus Cryptococcus neoformans is the causative 53 agent of fatal meningitis most often in patients with defects in cell mediated immunity, including 54 transplant recipients and those living with HIV/AIDS (3-6). C. neoformans is responsible of the 55 15% of AIDS-related deaths (6). Treatment of cryptococcosis is difficult and therapeutic options 56 are limited. Even the best combination treatment using Amphotericin B with 5-fluorocytosine (5-57 FC) is not well tolerated, and 5-FC is often unavailable in resource-poor areas (7). Some of the 58 largest clinal challenges to invasive fungal infections are poor efficacy of the drugs, emerging 59 resistance issues, narrow selection and availability of antifungals especially in the areas where...

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“…The cryptococci capsule is composed of the polysaccharides glucuronoxylomannan (GXM) and glucuronoxylomannogalactan (GXMGal), with trace amounts of mannoproteins ( Bose et al, 2003 ; Wang et al, 2018 ). It has been observed that, specific antibodies against GXM interfere with capsular fibrils organization, potentially contributing to host defense ( Martinez et al, 2004 ; Agustinho et al, 2018 ). However, no drug capable of impairing capsule production and formation has been developed so far.…”

Section: Introductionmentioning

confidence: 99%

A Plumieridine-Rich Fraction From Allamanda polyantha Inhibits Chitinolytic Activity and Exhibits Antifungal Properties Against Cryptococcus neoformans

et al. 2020

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Cryptococcosis is a fungal infection caused mainly by the pathogenic yeasts Cryptococcus neoformans and Cryptococcus gattii . The infection initiates with the inhalation of propagules that are then deposited in the lungs. If not properly treated, cryptococci cells can disseminate and reach the central nervous system. The current recommended treatment for cryptococcosis employs a three-stage regimen, with the administration of amphotericin B, flucytosine and fluconazole. Although effective, these drugs are often unavailable worldwide, can lead to resistance development, and may display toxic effects on the patients. Thus, new drugs for cryptococcosis treatment are needed. Recently, an iridoid named plumieridine was found in Allamanda polyantha seed extract; it exhibited antifungal activity against C. neoformans with a MIC of 250 μg/mL. To address the mode of action of plumieridine, several in silico and in vitro experiments were performed. Through a ligand-based a virtual screening approach, chitinases were identified as potential targets. Confirmatory in vitro assays showed that C. neoformans cell-free supernatant incubated with plumieridine displayed reduced chitinase activity, while chitinolytic activity was not inhibited in the insoluble cell fraction. Additionally, confocal microscopy revealed changes in the distribution of chitooligomers in the cryptococcal cell wall, from a polarized to a diffuse cell pattern state. Remarkably, further assays have shown that plumieridine can also inhibit the chitinolytic activity from the supernatant and cell-free extracts of bacteria, insect and mouse-derived macrophage cells (J774.A1). Together, our results suggest that plumieridine can be a broad-spectrum chitinase inhibitor.

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Peeling the onion: the outer layers of Cryptococcus neoformans

Cited by 47 publications

References 132 publications

The Fungal Cell Wall: Candida, Cryptococcus, and Aspergillus Species

The Fungal Cell Wall: Candida, Cryptococcus, and Aspergillus Species

Puf4 Mediates Post-transcriptional Regulation of Caspofungin Resistance inCryptococcus neoformans

A Plumieridine-Rich Fraction From Allamanda polyantha Inhibits Chitinolytic Activity and Exhibits Antifungal Properties Against Cryptococcus neoformans

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