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Published on: July 25, 2022
Cryptococcus extracellular vesicles properties and their use as vaccine platforms
Juliana Rizzo1, Sarah Sze Wah Wong2, Anastasia D Gazi3
1Unité Biologie des ARN des Pathogènes Fongiques Département de Mycologie, Institut Pasteur, F-75015 Paris France.
Abstract:
Whereas extracellular vesicle (EV) research has become commonplace in different biomedical fields, this field of research is still in its infancy in mycology. Here we provide a robust set of data regarding the structural and compositional aspects of EVs isolated from the fungal pathogenic species Cryptococcus neoformans, C. deneoformans and C. deuterogattii. Using cutting-edge methodological approaches including cryogenic electron microscopy and cryogenic electron tomography, proteomics, and flow cytometry, we revisited cryptococcal EV features and suggest a new EV structural model, in which the vesicular lipid bilayer is covered by mannoprotein-based fibrillar decoration, bearing the capsule polysaccharide as its outer layer. About 10% of the EV population is devoid of fibrillar decoration, adding another aspect to EV diversity. By analysing EV protein cargo from the three species, we characterized the typical Cryptococcus EV proteome. It contains several membrane-bound protein families, including some Tsh proteins bearing a SUR7/PalI motif. The presence of known protective antigens on the surface of Cryptococcus EVs, resembling the morphology of encapsulated virus structures, suggested their potential as a vaccine. Indeed, mice immunized with EVs obtained from an acapsular C. neoformans mutant strain rendered a strong antibody response in mice and significantly prolonged their survival upon C. neoformans infection.
Insights
Extracellular vesicles (EVs) from pathogenic fungi like Cryptococcus have a novel structure with mannoprotein decoration. These fungal EVs show potential as a vaccine, prolonging survival in mice infected with Cryptococcus.
Area of Science:
- Mycology
- Microbiology
- Immunology
- Structural Biology
Background:
- Extracellular vesicle (EV) research is emerging in mycology, with limited understanding of fungal EVs.
- Pathogenic fungi like Cryptococcus are significant human pathogens, necessitating novel therapeutic strategies.
Purpose of the Study:
- To structurally and compositionally characterize extracellular vesicles (EVs) from pathogenic fungal species: Cryptococcus neoformans, C. deneoformans, and C. deuterogattii.
- To propose a new model for cryptococcal EV structure and analyze their protein cargo.
- To evaluate the vaccine potential of Cryptococcus EVs.
Main Methods:
- Cryogenic electron microscopy (cryo-EM) and cryogenic electron tomography (cryo-ET) for high-resolution structural analysis.
- Proteomics to identify protein composition of EVs.
- Flow cytometry for characterizing EV populations.
- Immunization studies in mice using acapsular Cryptococcus EVs.
Main Results:
- A novel structural model for fungal EVs was proposed: a lipid bilayer covered by mannoprotein fibrils and an outer layer of capsule polysaccharide.
- Approximately 10% of the EV population lacked fibrillar decoration, indicating EV diversity.
- The typical Cryptococcus EV proteome was characterized, including membrane-bound proteins like Tsh.
- EVs from an acapsular Cryptococcus neoformans mutant elicited a strong antibody response and significantly prolonged survival in infected mice.
Conclusions:
- Cryptococcus EVs possess a unique structure with potential as a vaccine candidate against fungal infections.
- The characterized EV proteome and structure provide a foundation for further research into fungal EVs.
- EV-based vaccines could offer a promising strategy for combating Cryptococcus infections.
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