Pathogen-derived extracellular vesicles mediate "Division of Labour" virulence in the fatal human fungus Cryptococcus gattii

Background: Cryptococcus gattii is a fungal pathogen that can cause fatal infections in both immunocompromised and immunocompetent humans and other animals. The Pacific Northwest outbreak of cryptococcosis, which started in 1999, was caused by a hypervirulent C. gattii lineage and led to over 500 li...

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Bibliographic Details
Published inJournal of extracellular vesicles Vol. 7; p. 113
Main Authors Bielska, Ewa, Sisquella, Marta Arch, Aldeieg, Maha, Birch, Charlotte, O'Donoghue, Eloise, May, Robin C
Format Journal Article
LanguageEnglish
Published Abingdon John Wiley & Sons, Inc 01.01.2018
Subjects
Cell proliferation
Cryptococcosis
Cryptococcus gattii
Deoxyribonucleic acid
Division of labor
DNA
Electron microscopy
Endocytosis
Extracellular vesicles
Fungi
Leukocytes
Macrophages
Outbreaks
Pathogens
Phagocytes
Phagosomes
Ribonucleic acid
RNA
Ultracentrifugation
Virulence
Pacific Northwest
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Summary:Background: Cryptococcus gattii is a fungal pathogen that can cause fatal infections in both immunocompromised and immunocompetent humans and other animals. The Pacific Northwest outbreak of cryptococcosis, which started in 1999, was caused by a hypervirulent C. gattii lineage and led to over 500 life-threatening infections. Recent data has shown that the hypervirulence of this lineage results from a unique "Division of Labour" mechanism within the fungal population which drives tremendously fast growth of the pathogen within phagocytic cells. In this process, non-replicating "guardian" cells protect the pathogens from the hostile environment of the macrophages, but the mechanism by which this occurs remains enigmatic. Methods: To study "Division of Labour" we used in vitro co-infection assays with fluorescently labeled cryptococcal strains and transwell systems to test the hypothesis that the presence of secreted effectors may enhance fungal proliferation. Extracellular vesicles (EVs) from the outbreakC. gattii strain R265 and non-pathogenic ICB180 were isolated using ultracentrifugation, followed by characterization using electron microscopy and NanoSight NTA and visualized by fluorescence microscope using antibodies specific for cryptococcal capsule localized in the EVs. Results: We found that the mechanism of cooperation between individual cryptococci relies on the exchange of EVs between the fungal strains and can be triggered over large cellular distances. The mechanism is specific for the outbreak strain and not for non-pathogenic counterparts. EVs isolated from the outbreak strain of C. gattii are internalized promptly by white blood cells via endocytosis and taken up to phagosomes where they induce rapid proliferation of non-pathogenic cells in vitro. The effect is mediated by exosomal proteins and RNA, and not by exosomal DNA or capsular materials. Summary/Conclusion: To our knowledge, we demonstrate for the first time that fungal EVs are involved in virulence mechanisms that can be conferred over large distances within fungal populations.
ISSN:2001-3078