Cryptococcus neoformans glucuronoxylomannan and sterylglucoside are required for host protection in an animal vaccination model

Caroline Colombo Ana Caroline Colombo, Antonella Rella, Tyler Normile, Luna S. Joffe, Patricia M. Tavares, Glauber R. Glauber, Susana Frases, Erika P. Orner, Amir M. Farnoud, Bettina C. Fries, Brian Sheridan, Leonardo Nimrichter, Marcio L. Rodrigues, Maurizio Del Poeta

Research output: Contribution to journalArticlepeer-review

14 Scopus citations

Abstract

Cryptococcus neoformans is an encapsulated fungal pathogen that causes meningoencephalitis. There are no prophylactic tools for cryptococcosis. Previously, our group showed that a C. neoformans mutant lacking the gene encoding sterylglucosidase (Δsgl1) induced protection in both immunocompetent and immunocompromised murine models of cryptococcosis. Since sterylglucosidase catalyzes degradation of sterylglucosides (SGs), accumulation of this glycolipid could be responsible for protective immunity. In this study, we analyzed whether the activity of SGs is sufficient for the protective effect induced by the Δsgl1 strain. We observed that the accumulation of SGs impacted several properties of the main polysaccharide that composes the fungal capsule, glucuronoxylomannan (GXM). We therefore used genetic manipulation to delete the SGL1 gene in the acapsular mutant Δcap59 to generate a double mutant (strain Δcap59/Δsgl1) that was shown to be nonpathogenic and cleared from the lung of mice within 7 days post-intranasal infection. The inflammatory immune response triggered by the Δcap59/Δsgl1 mutant in the lung differed from the response seen with the other strains. The double mutant did not induce protection in a vaccination model, suggesting that SG-related protection requires the main capsular polysaccharide. Finally, GXM-containing extracellular vesicles (EVs) enriched in SGs delayed the acute lethality of Galleria mellonella against C. neoformans infection. These studies highlighted a key role for GXM and SGs in inducing protection against a secondary cryptococcal infection, and, since EVs notoriously contain GXM, these results suggest the potential use of Δsgl1 EVs as a vaccination strategy for cryptococcosis. IMPORTANCE The number of deaths from cryptococcal meningitis is around 180,000 per year. The disease is the second leading cause of mortality among individuals with AIDS. Antifungal treatment is costly and associated with adverse effects and resistance, evidencing the urgency of development of both therapeutic and prophylactic tools. Here we demonstrate the key roles of polysaccharide- and glycolipidcontaining structures in a vaccination model to prevent cryptococcosis.

Original languageEnglish (US)
Article numbere02909-18
JournalmBio
Volume10
Issue number2
DOIs
StatePublished - Mar 1 2019

Keywords

  • Capsule
  • Cryptococcus neoformans
  • Extracellular vesicles
  • Fungal infection
  • Glucuronoxylomannan
  • Glycolipids
  • Polysaccharides
  • Sterylglucosides
  • Vaccine
  • Vesicles

ASJC Scopus subject areas

  • Microbiology
  • Virology

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