Fungal Sugars and the Immune Response

Some of the world’s most dangerous pathogens hide behind sugar.Cryptococcus neoformans, a deadly fungus, surrounds itself in a complex polysaccharide called glucuronoxylomannan (GXM). This coating helps it evade the immune system and is key to its ability to cause disease.

We study the structure of GXM to understand how it interacts with the immune system. Using chemical synthesis, we develop tools to test how antibodies recognize GXM, revealing which oligosaccharide structures lead to protection and which don’t.

Recently, we identified a specific structure targeted by protective antibodies, offering a clue for designing better vaccines. We have also demonstrated that some antibodies can even break down GXM, suggesting new functions beyond our current understanding.

A big question we're working on is: how do different sugar shapes lead to different immune responses—protection, no effect, or even harmful outcomes? We think by linking structure to function, we can guide the rational design of vaccines and antibody therapies against fungal infections.

Selected Publications

1. Guazzelli, L. et al. A synthetic glycan array containing Cryptococcus neoformans glucuronoxylomannan capsular polysaccharide fragments allows the mapping of protective epitopes. Chem Sci 11, 9209–9217 (2020).
2. Crawford, C. J. et al. Semisynthetic Glycoconjugate Vaccine Candidates against Cryptococcus neoformans. ACS Infect Dis 10, 2089–2100 (2024).
3. Crawford, C. J. et al. A glycan FRET assay for detection and characterization of catalytic antibodies to the Cryptococcus neoformans capsule. Proc Natl Acad Sci U S A 118, e2016198118 (2021).
4. Hargett, A. A. et al. The structure of a C. neoformans polysaccharide motif recognized by protective antibodies: A combined NMR and MD study. Proc Natl Acad Sci U S A 121, e2315733121 (2024).
5. Crawford, C. J. et al. Synthetic Glycans Reveal Determinants of Antibody Functional Efficacy against a Fungal Pathogen. ACS Infect Dis 10, 475–488 (2024).