Is point mutagenesis a mechanism for antigenic variation in Trypanosoma brucei?
Antigenic variation in African trypanosomes proceeds by switching between different variant surface glycoprotein (VSG) molecules, whose extensive epitope differences enable evasion of antibody responses. Each trypanosome has approximately 1000 basic copy VSG genes inside chromosomes and a subset located at telomeres. Switching usually involves different individual basic copy genes being duplicated, as an expression linked copy, into a transcriptionally active site. In a few cases expression linked copies with a number of point mutations have been observed, leading to the suggestion that point mutagenesis provides another mechanism of antigenic variation. The most extensive example is a VSG gene that is normally activated in the metacyclic population in the tsetse fly, but the point mutations were detected in expression linked copies generated during bloodstream infection, after prolonged growth and selection. It was suggested that particularly telomeric or metacyclic VSG genes might undergo point mutagenesis during expression linked copy formation. To test this we have cloned 3 trypanosomes very soon after they had generated, during mouse infection, expression linked copies of the metacyclic VSG gene ILTat 1.22 and have detected only a single point mutation which is present in one expression linked copy, but not the corresponding basic copy, gene. This mutation does not prevent binding of a neutralizing antibody. Extensive VSG gene point mutagenesis may be a consequence merely of prolonged growth and extensive selection. There is not a single reported case of a point mutated VSG presenting a completely new set of exposed epitopes, suggesting point mutagenesis is unlikely to be an authentic mechanism for antigenic variation.
Graham
V S
VS
Wellcome Unit of Molecular Parasitology, University of Glasgow, Anderson College, UK.
Barry
J D
JD
D000818:Animals; D000940:Antigenic Variation; D000953:Antigens, Protozoan / Q000235:genetics*; D018076:DNA, Complementary / Q000235:genetics; D000939:Epitopes; D005069:Evaluation Studies as Topic; D015870:Gene Expression; D017125:Genes, Protozoan; D051379:Mice; D008957:Models, Genetic; D008969:Molecular Sequence Data; D016296:Mutagenesis; D017354:Point Mutation; D012641:Selection, Genetic; D017422:Sequence Analysis, DNA; D014346:Trypanosoma brucei brucei / Q000235:genetics*; D014353:Trypanosomiasis, African; D014643:Variant Surface Glycoproteins, Trypanosoma / Q000235:genetics*
D000953:Antigens, Protozoan; D018076:DNA, Complementary; D000939:Epitopes; D014643:Variant Surface Glycoproteins, Trypanosoma