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, F. Nina Papavasiliou, C. Erec Stebbins

Research output: Contribution to journalArticle

Abstract

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 (US)
Pages (from-to)932-938
Number of pages7
JournalNature Microbiology
Volume3
Issue number8
DOIs
StatePublished - Aug 1 2018

Fingerprint

Trypanosomiasis
Membrane Glycoproteins
Glycosylation
Antigenic Variation
Immunity
Parasites
Immune Evasion
Trypanosoma brucei brucei
Hexoses
Post Translational Protein Processing
Virulence
Amino Acid Sequence
Carbohydrates
Amino Acids
Antibodies
Proteins

ASJC Scopus subject areas

  • Microbiology
  • Immunology
  • Applied Microbiology and Biotechnology
  • Genetics
  • Microbiology (medical)
  • Cell Biology

Cite this

Pinger, J., Nešić, D., Ali, L., Aresta-Branco, F., Lilic, M., Chowdhury, S., ... Stebbins, C. E. (2018). African trypanosomes evade immune clearance by O-glycosylation of the VSG surface coat. Nature Microbiology, 3(8), 932-938. https://doi.org/10.1038/s41564-018-0187-6

African trypanosomes evade immune clearance by O-glycosylation of the VSG surface coat. / Pinger, Jason; Nešić, Dragana; Ali, Liaqat; Aresta-Branco, Francisco; Lilic, Mirjana; Chowdhury, Shanin; Kim, Hee Sook; Verdi, Joseph; Raper, Jayne; Ferguson, Michael A.J.; Papavasiliou, F. Nina; Stebbins, C. Erec.

In: Nature Microbiology, Vol. 3, No. 8, 01.08.2018, p. 932-938.

Research output: Contribution to journalArticle

Pinger, J, Nešić, D, Ali, L, Aresta-Branco, F, Lilic, M, Chowdhury, S, Kim, HS, Verdi, J, Raper, J, Ferguson, MAJ, Papavasiliou, FN & Stebbins, CE 2018, 'African trypanosomes evade immune clearance by O-glycosylation of the VSG surface coat', Nature Microbiology, vol. 3, no. 8, pp. 932-938. https://doi.org/10.1038/s41564-018-0187-6
Pinger, Jason ; Nešić, Dragana ; Ali, Liaqat ; Aresta-Branco, Francisco ; Lilic, Mirjana ; Chowdhury, Shanin ; Kim, Hee Sook ; Verdi, Joseph ; Raper, Jayne ; Ferguson, Michael A.J. ; Papavasiliou, F. Nina ; Stebbins, C. Erec. / African trypanosomes evade immune clearance by O-glycosylation of the VSG surface coat. In: Nature Microbiology. 2018 ; Vol. 3, No. 8. pp. 932-938.
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