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Abstract
The small molecule (molecular mass <900 Daltons) composition of extracellular vesicles (EVs) produced by the pathogenic fungus Cryptococcus gattii is unknown, which limits the understanding of the functions of cryptococcal EVs. In this study, we analyzed the composition of small molecules in samples obtained from solid cultures of C. gattii by a combination of chromatographic and spectrometric approaches, and untargeted metabolomics. This analysis revealed previously unknown components of EVs, including small peptides with known biological functions in other models. The peptides found in C. gattii EVs had their chemical structure validated by chemical approaches and comparison with authentic standards, and their functions tested in a Galleria mellonella model of cryptococcal infection. One of the vesicular peptides (isoleucine-proline-isoleucine, Ile-Pro-Ile) improved the survival of G. mellonella lethally infected with C. gattii or C. neoformans. These results indicate that small molecules exported in EVs are biologically active in Cryptococcus. Our study is the first to characterize a fungal EV molecule inducing protection, pointing to an immunological potential of extracellular peptides produced by C. gattii.
Highlights
Cryptococcus gattii is a fungal pathogen that causes disease in immunocompetent individuals
extracellular vesicles (EVs) extracts were analyzed by ultrahigh performance liquid chromatography-tandem mass spectrometry (UHPLC-MS/MS), and the data submitted to molecular networking analysis in the Global Natural Product Social Molecular Networking (GNPS) platform, an interactive online small molecule–focused tandem mass spectrometry data curation and analysis infrastructure [14]
The knowledge of the functions of fungal EVs has continuously increased in the recent years [7], but the biological roles of low mass structures exported in EVs are unknown
Summary
Cryptococcus gattii is a fungal pathogen that causes disease in immunocompetent individuals. This fungus was responsible for outbreaks in the Pacific Northwest and in the Vancouver Island [1]. C. gattii can cause severe lung disease and death without dissemination. Its sibling species C. neoformans disseminates readily to the central nervous system (CNS) and causes death from meningoencephalitis [1]. C. gattii and C. neformans share major virulence determinants, including the ability to produce extracellular vesicles (EVs) [4,5,6]. EVs are membranous structures produced by prokaryotes and eukaryotes, including 14 fungal genera [7].
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