title: Candida albicans and its metabolite gliotoxin inhibit platelet function via interaction with thiols.
abstract: Platelets bind to Candida albicans, the major cause of candidiasis. But in contrast to other microorganisms the fungus does not aggregate platelets. Gliotoxin (GT), which possesses immunosuppressive properties, is produced by various fungi, including the opportunistic pathogens Aspergillus fumigatus and C. albicans . Its mode of action involves the formation of mixed disulfides with host proteins. Disulfide exchanges play an important role in platelet activation. Therefore, the effect of C. albicans and GT on platelet function was tested. C. albicans yeast cells (5,000-10,000 cells/microl) and GT, in pathophysiologically relevant concentrations (0.05-0.5 microM), inhibited platelet fibrinogen binding, anti gp IIb/IIIa antibody PAC-1 binding, aggregation and procoagulant activity in a dose-dependent manner. Alpha granule release, measured via CD62P surface expression, was not affected. Addition of reduced glutathione partially counteracted the effect of C. albicans and GT on platelet fibrinogen binding and platelet aggregation. The C. albicans metabolite GT features antithrombotic properties in addition to its immunosuppressive functions. Since treatment with reduced glutathione partially counteracted the inhibitory effect of C. albicans yeast cells and GT on platelet fibrinogen binding, the antithrombotic activity is likely to depend on the disulfide bridge of this mycotoxin. GT production by C. albicans could contribute to its survival in the blood stream during vascular infections. The knowledge of the underlying mechanisms of the antithrombotic properties might help to treat fungal infections as well as thrombosis.
authors.affiliation: Department of Anaesthesiology and Intensive Care, Experimental and Clinical Haemostasis, University of Muenster, Muenster, Germany.
authors.forename: Anne
authors.initials: A
authors.lastname: Bertling
authors.forename: Silke
authors.initials: S
authors.lastname: Niemann
authors.forename: Andreas
authors.initials: A
authors.lastname: Uekötter
authors.forename: Wolfgang
authors.initials: W
authors.lastname: Fegeler
authors.forename: Cornelia
authors.initials: C
authors.lastname: Lass-Flörl
authors.forename: Christof
authors.initials: C
authors.lastname: von Eiff
authors.forename: Beate E
authors.initials: BE
authors.lastname: Kehrel
mesh_terms: D000911:Antibodies, Monoclonal / Q000378:metabolism; D001777:Blood Coagulation; D001792:Blood Platelets / Q000187:drug effects / Q000276:immunology / Q000378:metabolism*; D002176:Candida albicans / Q000378:metabolism*; D004305:Dose-Response Relationship, Drug; D005340:Fibrinogen / Q000378:metabolism; D005343:Fibrinolytic Agents / Q000378:metabolism* / Q000494:pharmacology; D005912:Gliotoxin / Q000378:metabolism* / Q000494:pharmacology; D005978:Glutathione / Q000378:metabolism; D006801:Humans; D019007:P-Selectin / Q000378:metabolism; D015539:Platelet Activation; D010974:Platelet Aggregation; D019039:Platelet Glycoprotein GPIIb-IIIa Complex / Q000276:immunology / Q000378:metabolism; D013438:Sulfhydryl Compounds / Q000378:metabolism*; D013997:Time Factors
chemical_list: D000911:Antibodies, Monoclonal; D005343:Fibrinolytic Agents; D019007:P-Selectin; D019039:Platelet Glycoprotein GPIIb-IIIa Complex; D013438:Sulfhydryl Compounds; D005912:Gliotoxin; D005340:Fibrinogen; D005978:Glutathione