α- and β-1,3-Glucan Synthesis and Remodeling

Wagener, Johannes; Striegler, Kristina; Wagener, Nikola

doi:10.1007/82_2020_200

Cited by 15 publications

(18 citation statements)

References 161 publications

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“…Fungal cell wall β-glucan is also an important pathogen-associated molecular pattern (PAMP). To avoid the innate immune response, many fungal pathogens depend on the synthesis of the cell wall α-glucan, which functions as a stealth molecule to mask the β-glucans itself or links other masking structures to the cell wall [56]. As demonstrated in the previous results, when we inhibited the PbDrk1 pathway, the Pb18 yeast underwent changes in their cell wall composition.…”

Section: Inhibition Of Pbdrk1 Induces Increased Phagocytosis Of P Brasiliensis and Alters Cytokine Production By Macrophagessupporting

confidence: 53%

The Role of Dimorphism Regulating Histidine Kinase (Drk1) in the Pathogenic Fungus Paracoccidioides brasiliensis Cell Wall

Navarro

Barros

Segura

et al. 2021

JoF

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Dimorphic fungi of the Paracoccidioides genus are the causative agents of paracoccidioidomycosis (PCM), an endemic disease in Latin America with a high incidence in Brazil. This pathogen presents as infective mycelium at 25 °C in the soil, reverting to its pathogenic form when inhaled by the mammalian host (37 °C). Among these dimorphic fungal species, dimorphism regulating histidine kinase (Drk1) plays an essential role in the morphological transition. These kinases are present in bacteria and fungi but absent in mammalian cells and are important virulence and cellular survival regulators. Hence, the purpose of this study was to investigate the role of PbDrk1 in the cell wall modulation of P. brasiliensis. We observed that PbDrk1 participates in fungal resistance to different cell wall-disturbing agents by reducing viability after treatment with iDrk1. To verify the role of PbDRK1 in cell wall morphogenesis, qPCR results showed that samples previously exposed to iDrk1 presented higher expression levels of several genes related to cell wall modulation. One of them was FKS1, a β-glucan synthase that showed a 3.6-fold increase. Furthermore, confocal microscopy analysis and flow cytometry showed higher β-glucan exposure on the cell surface of P. brasiliensis after incubation with iDrk1. Accordingly, through phagocytosis assays, a significantly higher phagocytic index was observed in yeasts treated with iDrk1 than the control group, demonstrating the role of PbDrk1 in cell wall modulation, which then becomes a relevant target to be investigated. In parallel, the immune response profile showed increased levels of proinflammatory cytokines. Finally, our data strongly suggest that PbDrk1 modulates cell wall component expression, among which we can identify β-glucan. Understanding this signalling pathway may be of great value for identifying targets of antifungal molecular activity since HKs are not present in mammals.

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Section: Inhibition Of Pbdrk1 Induces Increased Phagocytosis Of P Brasiliensis and Alters Cytokine Production By Macrophagessupporting

confidence: 53%

The Role of Dimorphism Regulating Histidine Kinase (Drk1) in the Pathogenic Fungus Paracoccidioides brasiliensis Cell Wall

Navarro

Barros

Segura

et al. 2021

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“…Degradation of BDG has been observed in phagocytic cells and is presumed to occur chemically, through hydrolytic mechanisms [23]. Some of the myriad functions of BDG include use as a cell wall structural material in fungi [24], as Inactivation, or elimination, of the endotoxin-specific components of the cascade renders it exclusively sensitive to BDG, permitting the creation of a reagent suitable for laboratory assays for BDG [14,15]. These assays have been established, commercially, using kinetic photometric methods [16].…”

Section: (1→3)-β-glucan Distribution and Structurementioning

confidence: 99%

Section: (1→3)-β-glucan Distribution and Structurementioning

confidence: 99%

“…Degradation of BDG has been observed in phagocytic cells and is presumed to occur chemically, through hydrolytic mechanisms [23]. Some of the myriad functions of BDG include use as a cell wall structural material in fungi [24], as extra-cellular and intra-cellular matrix material in certain bacteria [25], and algae [26], respectively. In plants, it appears as a wound repair and specialized structural material [27], typically in wound response tissue [28], vascular elements [29], and as intracellular pressure regulators in plasmodesmata [30].…”

Section: (1→3)-β-glucan Distribution and Structurementioning

confidence: 99%

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Specificity Influences in (1→3)-β-d-Glucan-Supported Diagnosis of Invasive Fungal Disease

Finkelman

2020

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(1→3)-β-glucan (BDG) testing as an adjunct in the diagnosis of invasive fungal disease (IFD) has been in use for nearly three decades. While BDG has a very high negative predictive value in this setting, diagnostic false positives may occur, limiting specificity and positive predictive value. Although results may be diagnostically false positive, they are analytically correct, due to the presence of BDG in the circulation. This review surveys the non-IFD causes of elevated circulating BDG. These are in the main, iatrogenic patient contamination through the use of BDG-containing medical devices and parenterally-delivered materials as well as translocation of intestinal luminal BDG due to mucosal barrier injury. Additionally, infection with Nocardia sp. may also contribute to elevated circulating BDG. Knowledge of the factors which may contribute to such non-IFD-related test results can improve the planning and interpretation of BDG assays and permit investigational strategies, such as serial sampling and BDG clearance evaluation, to assess the likelihood of contamination and improve patient care.

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“…Echinocandins target an essential element of the fungal cell wall by inhibition of the β-1,3- d -glucan synthase, which results in a fungicidal effect on Candida spp. 16 , 17 Unlike C. albicans , C. glabrata harbours two FKS genes, FKS 1 and FKS 2, which are considered functionally redundant. 18 , 19 Echinocandin resistance is mainly conferred by point mutations leading to amino acid substitutions within the two hot spots (HS) of the enzyme’s catalytic subunits encoded by FKS1 and FKS2 , which result in a substantial reduction of echinocandin affinity for its target enzyme.…”

Section: Introductionmentioning

confidence: 99%

Emergence of resistantCandida glabratain Germany

Aldejohann

Herz

Martin

et al. 2021

JAC-Antimicrobial Resistance

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Background Candida glabrata is the second leading fungal pathogen causing candidaemia and invasive candidiasis in Europe. This yeast is recognized for its rapid ability to acquire antifungal drug resistance. Objectives We systematically evaluated 176 C. glabrata isolates submitted to the German National Reference Center for Invasive Fungal Infections (NRZMyk) between 2015 and 2019 with regard to echinocandin and fluconazole susceptibility. Methods Susceptibility testing was performed using a reference protocol (EUCAST) and a range of commercial assays. Hot spot regions of the echinocandin target FKS genes were sequenced using Sanger sequencing. Results In total, 84 of 176 isolates were initially classified as anidulafungin-resistant based on EUCAST testing. Of those, 71 harboured mutations in the glucan synthase encoding FKS genes (13% in FKS1, 87% in FKS2). Significant differences in anidulafungin MICs were found between distinct mutation sites. 11 FKS wild-type (WT) isolates initially classified as resistant exhibited anidulafungin MICs fluctuating around the interpretation breakpoint upon re-testing with multiple assays. Two FKS WT isolates consistently showed high anidulafungin MICs and thus must be considered resistant despite the absence of target gene mutations. Over one-third of echinocandin-resistant strains displayed concomitant fluconazole resistance. Of those, isolates linked to bloodstream infection carrying a change at Ser-663 were associated with adverse clinical outcome. Conclusions Resistant C. glabrata strains are emerging in Germany. Phenotypic echinocandin testing can result in misclassification of susceptible strains. FKS genotyping aids in detecting these strains, however, echinocandin resistance may occur despite a wild-type FKS genotype.

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α- and β-1,3-Glucan Synthesis and Remodeling

Cited by 15 publications

References 161 publications

The Role of Dimorphism Regulating Histidine Kinase (Drk1) in the Pathogenic Fungus Paracoccidioides brasiliensis Cell Wall

The Role of Dimorphism Regulating Histidine Kinase (Drk1) in the Pathogenic Fungus Paracoccidioides brasiliensis Cell Wall

Specificity Influences in (1→3)-β-d-Glucan-Supported Diagnosis of Invasive Fungal Disease

Emergence of resistantCandida glabratain Germany

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