Carbohydrate-binding agents act as potent trypanocidals that elicit modifications in VSG glycosylation and reduced virulence in Trypanosoma brucei.
The surface of Trypanosoma brucei is covered by a dense coat of glycosylphosphatidylinositol-anchored glycoproteins. The major component is the variant surface glycoprotein (VSG) which is glycosylated by both paucimannose and oligomannose N-glycans. Surface glycans are poorly accessible and killing mediated by peptide lectin-VSG complexes is hindered by active endocytosis. However, contrary to previous observations, here we show that high-affinity carbohydrate binding agents bind to surface glycoproteins and abrogate growth of T. brucei bloodstream forms. Specifically, binding of the mannose-specific Hippeastrum hybrid agglutinin (HHA) resulted in profound perturbations in endocytosis and parasite lysis. Prolonged exposure to HHA led to the loss of triantennary oligomannose structures in surface glycoproteins as a result of genetic rearrangements that abolished expression of the oligosaccharyltransferase TbSTT3B gene and yielded novel chimeric enzymes. Mutant parasites exhibited markedly reduced infectivity thus demonstrating the importance of specific glycosylation patterns in parasite virulence.
Instituto de Parasitología y Biomedicina 'López-Neyra'. Consejo Superior de Investigaciones Científicas, Parque Tecnológico de Ciencias de la Salud, Avenida del Conocimiento, s/n 18016, Armilla, Granada, Spain.
Víctor M
VM
Castillo-Acosta
Antonio E
AE
Vidal
Luis M
LM
Ruiz-Pérez
Els J M
EJ
Van Damme
Yasuhiro
Y
Igarashi
Jan
J
Balzarini
Dolores
D
González-Pacanowska
D000818:Animals; D002453:Cell Cycle / Q000187:drug effects; D002460:Cell Line; D004195:Disease Models, Animal; D004705:Endocytosis / Q000187:drug effects; D006031:Glycosylation; D006801:Humans; D019668:Liliaceae; D037241:Mannose-Binding Lectins / Q000378:metabolism / Q000494:pharmacology*; D008364:Mannosyltransferases / Q000235:genetics / Q000378:metabolism; D051379:Mice; D008810:Mice, Inbred C57BL; D014344:Trypanocidal Agents / Q000378:metabolism / Q000494:pharmacology*; D014346:Trypanosoma brucei brucei / Q000187:drug effects* / Q000235:genetics / Q000378:metabolism / Q000472:pathogenicity; D014353:Trypanosomiasis, African / Q000188:drug therapy / Q000469:parasitology; D014643:Variant Surface Glycoproteins, Trypanosoma / Q000737:chemistry / Q000378:metabolism*; D014774:Virulence / Q000187:drug effects
D037241:Mannose-Binding Lectins; D014344:Trypanocidal Agents; D014643:Variant Surface Glycoproteins, Trypanosoma; D008364:Mannosyltransferases