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The African trypanosome Trypanosoma brucei spp. is a paradigm for antigenic variation, the orchestrated alteration of cell surface molecules to evade host immunity. The parasite elicits robust antibody-mediated immune responses to its variant surface glycoprotein (VSG) coat, but evades immune clearance by repeatedly accessing a large genetic VSG repertoire and ‘switching’ to antigenically distinct VSGs. This persistent immune evasion has been ascribed exclusively to amino-acid variance on the VSG surface presented by a conserved underlying protein architecture. We establish here that this model does not account for the scope of VSG structural and biochemical diversity. The 1.4-Å-resolution crystal structure of the variant VSG3 manifests divergence in the tertiary fold and oligomeric state. The structure also reveals an O-linked carbohydrate on the top surface of VSG3. Mass spectrometric analysis indicates that this O-glycosylation site is heterogeneously occupied in VSG3 by zero to three hexose residues and is also present in other VSGs. We demonstrate that this O-glycosylation increases parasite virulence by impairing the generation of protective immunity. These data alter the paradigm of antigenic variation by the African trypanosome, expanding VSG variability beyond amino-acid sequence to include surface post-translational modifications with immunomodulatory impact.
|Number of pages||7|
|Early online date||9 Jul 2018|
|Publication status||Published - Aug 2018|
ASJC Scopus subject areas
- Applied Microbiology and Biotechnology
- Microbiology (medical)
- Cell Biology
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- 1 Active
Protein Glycosylation in Trypanosomes: Defining and Exploiting a Biological System (Senior Investigator Award)
1/10/13 → 30/06/23
- Biological Chemistry and Drug Discovery - Regius Professor of Life Sciences & Molecular Parasitology