Surface localization of glucosylceramide during Cryptococcus neoformans infection allows targeting as a potential antifungal

Cryptococcus neoformans (Cn) is a significant human pathogen that, despite current treatments, continues to have a high morbidity rate especially in sub-Saharan Africa. The need for more tolerable and specific therapies has been clearly shown. In the search for novel drug targets, the gene for gluco...

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Bibliographic Details
Published in:PloS one 2011-01, Vol.6 (1), p.e15572-e15572
Main Authors: Rhome, Ryan, Singh, Arpita, Kechichian, Talar, Drago, Monica, Morace, Giulia, Luberto, Chiara, Del Poeta, Maurizio
Format: Article
Language:English
Subjects:
Animal models
Animals
Antibiotics
Antifungal agents
Antifungal Agents - therapeutic use
Biochemistry
Biological activity
Biology
Carbon dioxide
Cell Membrane - metabolism
Cell surface
Ceramide glucosyltransferase
Cryptococcosis - drug therapy
Cryptococcus neoformans
Cryptococcus neoformans - drug effects
Cryptococcus neoformans - pathogenicity
Disease
Drug development
Enzymes
Fungal infections
Fungi
Fungicides
Glucosylceramidase - deficiency
Glucosylceramidase - metabolism
Glucosylceramidase - pharmacology
Glucosylceramidase - therapeutic use
Glucosylceramides - metabolism
Glucosyltransferases - deficiency
Glucosyltransferases - genetics
Health aspects
Immunofluorescence
Immunoglobulins
Infections
Kinases
Laboratories
Lipids
Localization
Lungs
Medicine
Mice
Molecular biology
Morbidity
Mortality
pH effects
Pichia pastoris
Sterols
Studies
Therapeutic applications
Therapeutics
Treatment Outcome
Vaccines
Virulence
Virulence (Microbiology)
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Summary:Cryptococcus neoformans (Cn) is a significant human pathogen that, despite current treatments, continues to have a high morbidity rate especially in sub-Saharan Africa. The need for more tolerable and specific therapies has been clearly shown. In the search for novel drug targets, the gene for glucosylceramide synthase (GCS1) was deleted in Cn, resulting in a strain (Δgcs1) that does not produce glucosylceramide (GlcCer) and is avirulent in mouse models of infection. To understand the biology behind the connection between virulence and GlcCer, the production and localization of GlcCer must be characterized in conditions that are prohibitive to the growth of Δgcs1 (neutral pH and high CO(2)). These prohibitive conditions are physiologically similar to those found in the extracellular spaces of the lung during infection. Here, using immunofluorescence, we have shown that GlcCer localization to the cell surface is significantly increased during growth in these conditions and during infection. We further seek to exploit this localization by treatment with Cerezyme (Cz), a recombinant enzyme that metabolizes GlcCer, as a potential treatment for Cn. Cz treatment was found to reduce the amount of GlcCer in vitro, in cultures, and in Cn cells inhabiting the mouse lung. Treatment with Cz induced a membrane integrity defect in wild type Cn cells similar to Δgcs1. Cz treatment also reduced the in vitro growth of Cn in a dose and condition dependent manner. Finally, Cz treatment was shown to have a protective effect on survival in mice infected with Cn. Taken together, these studies have established the legitimacy of targeting the GlcCer and other related sphingolipid systems in the development of novel therapeutics.
ISSN:1932-6203
1932-6203
DOI:10.1371/journal.pone.0015572