African trypanosomes evade immune clearance by O-glycosylation of the VSG surface coat

Jason Pinger, Dragana Nešić, Liaqat Ali, Francisco Aresta-Branco, Mirjana Lilic, Shanin Chowdhury, Hee Sook Kim, Joseph Verdi, Jayne Raper, Michael A.J. Ferguson (Lead / Corresponding author), F. Nina Papavasiliou (Lead / Corresponding author), C. Erec Stebbins (Lead / Corresponding author)

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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.

Original languageEnglish
Pages (from-to)932-938
Number of pages7
JournalNature Microbiology
Issue number8
Early online date9 Jul 2018
Publication statusPublished - Aug 2018

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    Pinger, J., Nešić, D., Ali, L., Aresta-Branco, F., Lilic, M., Chowdhury, S., Kim, H. S., Verdi, J., Raper, J., Ferguson, M. A. J., Papavasiliou, F. N., & Stebbins, C. E. (2018). African trypanosomes evade immune clearance by O-glycosylation of the VSG surface coat. Nature Microbiology, 3(8), 932-938.