From silent genes to noisy populations-dialogue between the genotype and phenotypes of antigenic variation

Abstract

African trypanosomes evade humoral immunity through antigenic variation whereby, they switch expression of the variant surface glycoprotein (VSG) gene encoding their glycoprotein surface coat. Switching proceeds by duplication from an archive of silent VSG genes into a transcriptionally active locus, and precedent suggests silent genes can contribute, combinatorially to formation of expressed, functional genes through segmental gene conversion. The genome project has revealed that most of the silent archive consists of hundreds of VSG genes in subtelomeric tandem arrays, and that most of these are not functional genes. The aim of this review is to explore links between the uncovered trypanosome genotype and the phenotype of antigenic variation, stretching from the broad phenotype-transmission in the field and the overcoming of herd immunity-to events within single infections. Highlighting in particular the possible impact of phenotype selection on the evolution of the VSG archive and the mechanisms for its expression leads to a theoretical framework to further our understanding of this complex immune evasion strategy.

Fig. 1. Model framework for antigenic variation, from broad phenotype in the field to molecular information and mechanisms responsible for switching.

The model links all levels of antigenic variation, from molecular mechanisms to what happens in the field. Evolutionary pressure is exerted at the field level and results in selection for mechanisms and features lying lower within the system. Biological levels are displayed in the left column, and their elements subject to selection are shown in the right column. Features responsible for these elements, and proposed to link the levels, are displayed in the central column. MVAT: metacyclic variable antigen type (VSG type expressed by a metacyclic stage trypanosome).

Fig. 2. Sequential expression of variants in multiple infections.

Spreadsheet analysis of the data of (Capbern et al. 1977), who analyzed the appearance of 74 variants of Trypanosoma equiperdum in 11 rabbit infections. The curve with diamond symbols (left y-axis) shows the mean (±1 SEM) of the time of appearance of each variant in the rabbits, as measured by antibody responses against each variant. There is a gradual increase in these times, and neighbouring variants have closely similar times of appearance. These data concur with those of (Morrison et al. 2005), in that there is very little variance in the time of appearance of each variant. The data also resemble the continuum in sequential appearance of variants reported for T. vivax (Barry 1986), and do not support the conclusion of (Capbern et al. 1977) that variants fall into 3 timing groups; the gap between days 15 and 19, and between days 30 and 32, probably represent the remission phases between parasitaemia peaks. The curve with square symbols (right y-axis) represents the proportion of infections in which each variant appeared, and the two arrows show when two mosaic-encoded VSGs (Thon et al. 1990) were expressed. It is clear that, following the initial phase, there is a tendency towards infection-specific variants, and this begins when the first mosaic gene-encoded variant was detected. This pattern is consistent with the theory that distinct ‘strings’ of mosaics arise in distinct infections. The data have been corrected to compensate for the removal of some rabbits from the experiment at later stages of infection (Capbern et al. 1977).