UDP-glucose 4, 6-dehydratase Activity Plays an Important Role in Maintaining Cell Wall Integrity and Virulence of Candida albicans

ABSTRACTCurcumin (CUR) shows antifungal activity against a range of pathogenic fungi, includingCandida albicans. The reported mechanisms of action of CUR include reactive oxygen species (ROS) generation, defects in the ergosterol biosynthesis pathway, decrease in hyphal development, and modulation of multidrug efflux pumps. Reportedly, each of these pathways is independently linked to the cell wall machinery inC. albicans, but surprisingly, CUR has not been previously implicated in cell wall damage. In the present study, we performed transcriptional profiling to identify the yet-unidentified targets of CUR inC. albicans. We found that, among 348 CUR-affected genes, 51 were upregulated and 297 were downregulated. Interestingly, most of the cell wall integrity pathway genes were downregulated. The possibility of the cell wall playing a critical role in the mechanism of CUR required further validation; therefore, we performed specific experiments to establish if there was any link between the two. The fractional inhibitory concentration index values of 0.24 to 0.37 show that CUR interacts synergistically with cell wall-perturbing (CWP) agents (caspofungin, calcofluor white, Congo red, and SDS). Furthermore, we could observe cell wall damage and membrane permeabilization by CUR alone, as well as synergistically with CWP agents. We also found hypersusceptibility in calcineurin and mitogen-activated protein (MAP) kinase pathway mutants against CUR, which confirmed that CUR also targets cell wall biosynthesis inC. albicans. Together, these data provide strong evidence that CUR disrupts cell wall integrity inC. albicans. This new information on the mechanistic action of CUR could be employed in improving treatment strategies and in combinatorial drug therapy.

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Candida albicans Ecm33p Is Important for Normal Cell Wall Architecture and Interactions with Host Cells

Eukaryotic Cell ◽

10.1128/ec.5.1.140-147.2006 ◽

2006 ◽

Vol 5 (1) ◽

pp. 140-147 ◽

Cited By ~ 55

Author(s):

Raquel Martinez-Lopez ◽

Hyunsook Park ◽

Carter L. Myers ◽

Concha Gil ◽

Scott G. Filler

Keyword(s):

Endothelial Cells ◽

Cell Wall ◽

Candida Albicans ◽

Epithelial Cells ◽

Normal Cell ◽

Cell Wall Integrity ◽

Host Cells ◽

Epithelial Cell Line ◽

Oral Epithelial ◽

Cell Wall Architecture

ABSTRACT Candida albicans ECM33 encodes a glycosylphosphatidylinositol-linked cell wall protein that is important for cell wall integrity. It is also critical for normal virulence in the mouse model of hematogenously disseminated candidiasis. To identify potential mechanisms through which Ecm33p contributes to virulence, we investigated the interactions of C. albicans ecm33Δ mutants with endothelial cells and the FaDu oral epithelial cell line in vitro. The growth rate of blastospores of strains containing either one or no intact copies of ECM33 was 50% slower than that of strains containing two intact copies of ECM33. However, all strains germinated at the same rate, forming similar-length hyphae on endothelial cells and oral epithelial cells. Strains containing either one or no intact copies of ECM33 had modestly reduced adherence to both types of host cells, and a markedly reduced capacity to invade and damage these cells. Saccharomyces cerevisiae expressing C. albicans ECM33 did not adhere to or invade epithelial cells, suggesting that Ecm33p by itself does not act as an adhesin or invasin. Examination of ecm33Δ mutants by transmission electron microscopy revealed that the cell wall of these strains had an abnormally electron-dense outer mannoprotein layer, which may represent a compensatory response to reduced cell wall integrity. The hyphae of these mutants also had aberrant surface localization of the adhesin Als1p. Collectively, these results suggest that Ecm33p is required for normal cell wall architecture as well as normal function and expression of cell surface proteins in C. albicans.

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Cell wall integrity is linked to mitochondria and phospholipid homeostasis in Candida albicans through the activity of the post-transcriptional regulator Ccr4-Pop2

Molecular Microbiology ◽

10.1111/j.1365-2958.2010.07503.x ◽

2010 ◽

Vol 79 (4) ◽

pp. 968-989 ◽

Cited By ~ 82

Author(s):

Michael J. Dagley ◽

Ian E. Gentle ◽

Traude H. Beilharz ◽

Filomena A. Pettolino ◽

Julianne T. Djordjevic ◽

...

Keyword(s):

Cell Wall ◽

Candida Albicans ◽

Transcriptional Regulator ◽

Cell Wall Integrity

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The tricarboxylic acid cycle, cell wall integrity pathway, cytokinesis and intracellular pH homeostasis are involved in the sensitivity of Candida albicans cells to high levels of extracellular calcium

Genomics ◽

10.1016/j.ygeno.2018.08.001 ◽

2019 ◽

Vol 111 (6) ◽

pp. 1226-1230 ◽

Cited By ~ 2

Author(s):

Huihui Xu ◽

Malcolm Whiteway ◽

Linghuo Jiang

Keyword(s):

Cell Wall ◽

Candida Albicans ◽

Intracellular Ph ◽

Tricarboxylic Acid Cycle ◽

Tricarboxylic Acid ◽

Extracellular Calcium ◽

Cell Wall Integrity ◽

Ph Homeostasis ◽

Acid Cycle ◽

Cell Wall Integrity Pathway

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Comparative Lipidomics in Clinical Isolates of Candida albicans Reveal Crosstalk between Mitochondria, Cell Wall Integrity and Azole Resistance

PLoS ONE ◽

10.1371/journal.pone.0039812 ◽

2012 ◽

Vol 7 (6) ◽

pp. e39812 ◽

Cited By ~ 37

Author(s):

Ashutosh Singh ◽

Vipin Yadav ◽

Rajendra Prasad

Keyword(s):

Cell Wall ◽

Candida Albicans ◽

Cell Wall Integrity ◽

Clinical Isolates ◽

Azole Resistance

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Environmentally contingent control of Candida albicans cell wall integrity by transcriptional regulator Cup9

Genetics ◽

10.1093/genetics/iyab075 ◽

2021 ◽

Author(s):

Yuichi Ichikawa ◽

Vincent M Bruno ◽

Carol A Woolford ◽

Hannah Kim ◽

Eunsoo Do ◽

...

Keyword(s):

Cell Wall ◽

Candida Albicans ◽

Surface Protein ◽

Hyphal Growth ◽

Growth Conditions ◽

Cell Wall Integrity ◽

Yeast Growth ◽

Transcription Factor Genes ◽

A Cell ◽

Rna Levels

Abstract The fungal pathogen Candida albicans is surrounded by a cell wall that is the target of caspofungin and other echinocandin antifungals. C. albicans can grow in several morphological forms, notably budding yeast and hyphae. Yeast and hyphal forms differ in cell wall composition, leading us to hypothesize that there may be distinct genes required for yeast and hyphal responses to caspofungin. Mutants in 27 genes reported previously to be caspofungin hypersensitive under yeast growth conditions were all caspofungin hypersensitive under hyphal growth conditions as well. However, a screen of mutants defective in transcription factor genes revealed that Cup9 is required for normal caspofungin tolerance under hyphal and not yeast growth conditions. In a hyphal-defective efg1Δ/Δ background, Cup9 is still required for normal caspofungin tolerance. This result argues that Cup9 function is related to growth conditions rather than cell morphology. RNA-seq conducted under hyphal growth conditions indicated that 361 genes were up-regulated and 145 genes were down-regulated in response to caspofungin treatment. Both classes of caspofungin-responsive genes were enriched for cell wall-related proteins, as expected for a response to disruption of cell wall integrity and biosynthesis. The cup9Δ/Δ mutant, treated with caspofungin, had reduced RNA levels of 40 caspofungin up-regulated genes, and had increased RNA levels of 8 caspofungin down-regulated genes, an indication that Cup9 has a narrow rather than global role in the cell wall integrity response. Five Cup9-activated surface-protein genes have roles in cell wall integrity, based on mutant analysis published previously (PGA31, IFF11) or shown here (ORF19.3499, ORF19.851 or PGA28), and therefore may explain the hypersensitivity of the cup9Δ/Δ mutant to caspofungin. Our findings define Cup9 as a new determinant of caspofungin susceptibility.

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