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

ABSTRACT Candida albicans is an opportunistic human fungal pathogen and a causative agent of oropharyngeal candidiasis (OPC), the most frequent opportunistic infection among patients with AIDS. Fluconazole and other azole antifungal agents have proven effective in the management of OPC; however, with increased use of these agents treatment failures have occurred. Such failures have been associated with the emergence of azole-resistant strains of C. albicans. In the present study we examined changes in the genome-wide gene expression profile of a series of C. albicans clinical isolates representing the stepwise acquisition of azole resistance. In addition to genes previously associated with azole resistance, we identified many genes whose differential expression was for the first time associated with this phenotype. Furthermore, the expression of these genes was correlated with that of the known resistance genes CDR1, CDR2, and CaMDR1. Genes coordinately regulated with the up-regulation of CDR1 and CDR2 included the up-regulation of GPX1 and RTA3 and the down-regulation of EBP1. Genes coordinately regulated with the up-regulation of CaMDR1 included the up-regulation of IFD1, IFD4, IFD5, IFD7, GRP2, DPP1, CRD2, and INO1 and the down-regulation of FET34, OPI3, and IPF1222. Several of these appeared to be coordinately regulated with both the CDR genes and CaMDR1. Many of these genes are involved in the oxidative stress response, suggesting that reduced susceptibility to oxidative damage may contribute to azole resistance. Further evaluation of the role these genes and their respective gene products play in azole antifungal resistance is warranted.

Download Full-text

The key enzyme in galactose metabolism, UDP-galactose-4-epimerase, affects cell-wall integrity and morphology in Candida albicans even in the absence of galactose

Fungal Genetics and Biology ◽

10.1016/j.fgb.2006.11.006 ◽

2007 ◽

Vol 44 (6) ◽

pp. 563-574 ◽

Cited By ~ 27

Author(s):

Vijender Singh ◽

Somisetty V. Satheesh ◽

Mysore L. Raghavendra ◽

Parag P. Sadhale

Keyword(s):

Cell Wall ◽

Candida Albicans ◽

Cell Wall Integrity ◽

Galactose Metabolism ◽

Key Enzyme

Download Full-text

Protein phosphatase CaPpz1 is involved in cation homeostasis, cell wall integrity and virulence of Candida albicans

Microbiology ◽

10.1099/mic.0.057075-0 ◽

2012 ◽

Vol 158 (5) ◽

pp. 1258-1267 ◽

Cited By ~ 22

Author(s):

Csaba Ádám ◽

Éva Erdei ◽

Carlos Casado ◽

László Kovács ◽

Asier González ◽

...

Keyword(s):

Cell Wall ◽

Candida Albicans ◽

Protein Phosphatase ◽

Cell Wall Integrity ◽

Cation Homeostasis

Download Full-text

Curcumin Targets Cell Wall Integrity via Calcineurin-Mediated Signaling in Candida albicans

Antimicrobial Agents and Chemotherapy ◽

10.1128/aac.01385-13 ◽

2013 ◽

Vol 58 (1) ◽

pp. 167-175 ◽

Cited By ~ 48

Author(s):

Awanish Kumar ◽

Sanjiveeni Dhamgaye ◽

Indresh Kumar Maurya ◽

Ashutosh Singh ◽

Monika Sharma ◽

...

Keyword(s):

Cell Wall ◽

Candida Albicans ◽

Critical Role ◽

Pathogenic Fungi ◽

Cell Wall Integrity ◽

Ergosterol Biosynthesis ◽

Ros Generation ◽

Calcofluor White ◽

Content Type ◽

Cell Wall Damage

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.

Download Full-text

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.

Download Full-text