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

TY - JOUR

T1 - African trypanosomes evade immune clearance by O-glycosylation of the VSG surface coat

AU - Pinger, Jason

AU - Nešić, Dragana

AU - Ali, Liaqat

AU - Aresta-Branco, Francisco

AU - Lilic, Mirjana

AU - Chowdhury, Shanin

AU - Kim, Hee Sook

AU - Verdi, Joseph

AU - Raper, Jayne

AU - Ferguson, Michael A.J.

AU - Papavasiliou, F. Nina

AU - Stebbins, C. Erec

PY - 2018/8

Y1 - 2018/8

N2 - 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.

AB - 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.

U2 - 10.1038/s41564-018-0187-6

DO - 10.1038/s41564-018-0187-6

M3 - Article

C2 - 29988048

AN - SCOPUS:85049634691

SN - 2058-5276

VL - 3

SP - 932

EP - 938

JO - Nature Microbiology

JF - Nature Microbiology

IS - 8

ER -