Significant differences in the cell-wall mannans from three Candida glabrata strains correlate with antifungal drug sensitivity.

Department of Infection and Host Defense, Tohoku Pharmaceutical University, Aoba-ku, Sendai, Japan.
FEBS Journal (Impact Factor: 4.25). 03/2012; 279(10):1844-56. DOI: 10.1111/j.1742-4658.2012.08564.x
Source: PubMed

ABSTRACT Candida glabrata is often the second or third most common cause of candidiasis after Candida albicans. C. glabrata infections are difficult to treat, often resistant to many azole antifungal agents and are associated with a high mortality rate in compromised patients. We determined the antigenic structure of the cell-wall mannoproteins from three C. glabrata strains, NBRC 0005, NBRC 0622 and NBRC 103857. (1)H NMR and methylation analyses of the acetolysis products of these mannoproteins showed a significant difference in the amount of the β-1,2-linked mannose residue and side-chain structure. The C. glabrata NBRC 103857 strain contained up to the triose side chains and the nonreducing terminal of the triose was predominantly the β-1,2-linked mannose residue. By contrast, the mannans of the two former strains possessed up to the tetraose side chains and the amount of the β-1,2-linked mannose residue was very low. Larger oligosaccharides than tetraose in the acetolysis products of these mannans were identified as incomplete cleavage fragments by analyzing methylation, (1)H NMR spectra and the α1-2,3 mannosidase degradation reaction. Resistance to the antifungal drugs itraconazole and micafungin was significantly different in these strains. Interestingly, the NBRC 103857 strain, which involved a large amount of the β-1,2-linked mannose residues, exhibited significant sensitivity to these antifungal drugs.

  • Source
    [Show abstract] [Hide abstract]
    ABSTRACT: A large number of studies have been published over the last two decades examining molecular mechanisms of antifungal resistance in Candida species. However, few of these studies have explored how such mechanisms influence the host immune response to this opportunistic pathogen. With recent advances in our understanding of host immunity to Candida, a body of emerging literature has begun to explore how intrinsic and adaptive resistance mechanisms in Candida alter host immune system evasion and detection, which could have important implications for understanding (1) why certain resistance mechanisms and Candida species predominate in certain patient populations, (2) the biological context for understanding why high in vitro levels of resistance in may not necessarily correlate with risk of drug failure in vivo and (3) insight into effective immunotherapeutic strategies for combatting Candida resistance. Although this area of research is still in its infancy, two themes are emerging: First, the immunoevasion and intracellular persistence of C. glabrata may be a key factor in the capability of this species to persist in the course of multiple antifungal treatments and develop multidrug resistance. Second, changes in the cell wall associated with antifungal resistance often favor evasion for the host immune response.
    Virulence 07/2012; 3(4):368-76. · 2.79 Impact Factor
  • [Show abstract] [Hide abstract]
    ABSTRACT: The fungus Candida glabrata is an important and increasingly common pathogen of humans, particularly in immunocompromised hosts. Despite this little is known about the attributes that allow this organism to cause disease, or its interaction with the host immune system. However, in common with other fungi the cell wall of C. glabrata is the initial point of contact between the host and pathogen, and as such is likely to play an important role in mediating interactions and hence virulence. Here we show both through genetic complementation and polysaccharide structural analyses that C. glabrata ANP1, MNN2 and MNN11 encode functional orthologues of the respective Saccharomyces cerevisiae mannosyl-transferases. Furthermore we show that deletion of the C. glabrata Anp1, Mnn2 & Mnn11 mannosyltransferases, directly affects the structure of the fungal N-linked mannan, in-line with their predicted functions and this has implications for cell wall integrity and consequently virulence. C. glabrata anp1 and mnn2 mutants showed increased virulence, compared to wild-type (and mnn11) cells. This is in contrast to Candida albicans where inactivation of genes involved in mannan biosynthesis has usually been linked to an attenuation of virulence. In the longer-term better understanding of the attributes that allow C. glabrata to cause disease will provide insights that can be adopted for the development of novel therapeutic and diagnostic approaches.
    Journal of Biological Chemistry 05/2013; · 4.65 Impact Factor
  • [Show abstract] [Hide abstract]
    ABSTRACT: Protein secretion is an essential process for living organisms. In eukaryotes this encompasses numerous steps mediated by several hundred cellular proteins. The core functions of translocation through the endoplasmic reticulum membrane, primary glycosylation, folding and quality control, and vesicle mediated secretion are similar from yeasts to higher eukaryotes. However, recent research has revealed significant functional differences between yeasts and mammalian cells, and even among diverse yeast species. This review provides a current overview of the canonical protein secretion pathway in the model yeast Saccharomyces cerevisiae, highlighting differences to mammalian cells as well as currently unresolved questions, and provides a genomic comparison of the S. cerevisiae pathway to seven other yeast species where secretion has been investigated due to their attraction as protein production platforms, or for their relevance as pathogens. The analysis of Candida albicans, Candida glabrata, Kluyveromyces lactis, Pichia pastoris, Hansenula polymorpha, Yarrowia lipolytica, and Schizosaccharomyces pombe reveales that many - but not all - secretion steps are more redundant in S. cerevisiae due to duplicated genes, while some processes are even absent in this model yeast. Recent research obviates that even where homologous genes are present, small differences in protein sequence and/or differences in the regulation of gene expression may lead to quite different protein secretion phenotypes. © 2013 Federation of European Microbiological Societies. Published by Blackwell Publishing Ltd. All rights reserved.
    FEMS microbiology reviews 03/2013; · 10.96 Impact Factor