Cryptococcus neoformans Capsular GXM Conformation and Epitope Presentation: A Molecular Modelling Study

Molecules

Stefan Oscarson¹  MichelleM. Kuttel²  Arturo Casadevall³ 

[1] Centre for Synthesis and Chemical Biology, University College Dublin, Belfield, Dublin 4, Ireland;Department of Computer Science, University of Cape Town, Cape Town 7701, South Africa;Department of Molecular Microbiology and Immunology, Johns Hopkins Bloomberg School of Public Health, Johns Hopkins University, 615 N Wolfe St Room E5132, Baltimore, MD 21205, USA;

关键词: Cryptococcus neoformans;    conjugate vaccines;    GXM;    conformation;    capsular polysaccharide;    epitope;   

DOI  :  10.3390/molecules25112651

来源: DOAJ

【 摘 要 】

The pathogenic encapsulated Cryptococcus neoformans fungus causes serious disease in immunosuppressed hosts. The capsule, a key virulence factor, consists primarily of the glucuronoxylomannan polysaccharide (GXM) that varies in composition according to serotype. While GXM is a potential vaccine target, vaccine development has been confounded by the existence of epitopes that elicit non-protective antibodies. Although there is evidence for protective antibodies binding conformational epitopes, the secondary structure of GXM remains an unsolved problem. Here an array of molecular dynamics simulations reveal that the GXM mannan backbone is consistently extended and relatively inflexible in both C. neoformans serotypes A and D. Backbone substitution does not alter the secondary structure, but rather adds structural motifs: $\beta$ DGlcA and $\beta$ DXyl side chains decorate the mannan backbone in two hydrophillic fringes, with mannose-6-O-acetylation forming a hydrophobic ridge between them. This work provides mechanistic rationales for clinical observations—the importance of O-acetylation for antibody binding; the lack of binding of protective antibodies to short GXM fragments; the existence of epitopes that elicit non-protective antibodies; and the self-aggregation of GXM chains—indicating that molecular modelling can play a role in the rational design of conjugate vaccines.

【 授权许可】

Unknown