Antigenic diversity is generated by distinct evolutionary mechanisms in African trypanosome species

A. P. Jackson, A. Berry, M. Aslett, H. C. Allison, P. Burton, J. Vavrova-anderson, R. Brown, H. Browne, N. Corton, H. Hauser, J. Gamble, R. Gilderthorp, L. Marcello, J. Mcquillan, T. D. Otto, M. A. Quail, M. J. Sanders, A. Van Tonder, M. L. Ginger, M. C. FieldJ. D. Barry, C. Hertz-fowler, M. Berriman

Research output: Contribution to journalArticlepeer-review

115 Citations (Scopus)


Antigenic variation enables pathogens to avoid the host immune response by continual switching of surface proteins. The protozoan blood parasite Trypanosoma brucei causes human African trypanosomiasis (“sleeping sickness”) across sub-Saharan Africa and is a model system for antigenic variation, surviving by periodically replacing a monolayer of variant surface glycoproteins (VSG) that covers its cell surface. We compared the genome of Trypanosoma brucei with two closely related parasites Trypanosoma congolense and Trypanosoma vivax, to reveal how the variant antigen repertoire has evolved and how it might affect contemporary antigenic diversity. We reconstruct VSG diversification showing that Trypanosoma congolense uses variant antigens derived from multiple ancestral VSG lineages, whereas in Trypanosoma brucei VSG have recent origins, and ancestral gene lineages have been repeatedly co-opted to novel functions. These historical differences are reflected in fundamental differences between species in the scale and mechanism of recombination. Using phylogenetic incompatibility as a metric for genetic exchange, we show that the frequency of recombination is comparable between Trypanosoma congolense and Trypanosoma brucei but is much lower in Trypanosoma vivax. Furthermore, in showing that the C-terminal domain of Trypanosoma brucei VSG plays a crucial role in facilitating exchange, we reveal substantial species differences in the mechanism of VSG diversification. Our results demonstrate how past VSG evolution indirectly determines the ability of contemporary parasites to generate novel variant antigens through recombination and suggest that the current model for antigenic variation in Trypanosoma brucei is only one means by which these parasites maintain chronic infections.

Antigenic variation enables pathogens to evade immune responses by continual switching of surface proteins (1, 2). The African trypanosomes (Trypanosoma spp.) are vector-borne protozoan blood parasites that survive in their hosts by antigenic variation, periodically replacing a monolayer of variant surface glycoproteins (VSG) (3) that shield the cell surface from immune effectors (4, 5). Trypanosoma brucei is the cause of human African trypanosomiasis (or “sleeping sickness”), and the mechanisms for expression and dynamic replacement of VSG in this species are a model system for antigenic variation (4) as well as a classic example of adaptive evolution at the host–pathogen interface. Two related veterinary parasites, Trypanosoma congolense and Trypanosoma vivax, also use antigenic variation to cause devastating diseases in domesticated animals. Through their detrimental effects on livestock productivity, these species arguably represent greater threats to socioeconomic well-being than T. brucei does in the agrarian societies in which they are endemic. Our understanding of how antigenic diversity is organized in T. brucei was greatly improved by the T. brucei 927 reference genome sequence (6). In this paper, we present draft genome sequences for T. congolense and T. vivax; we define their global VSG repertoires in a three-way comparative analysis with T. brucei, revealing how antigenic diversity evolved in trypanosome genomes past and present.

The T. brucei genome includes many hundreds of VSG that encode a transcriptionally silent reservoir of variant antigens (6), and each cell expresses just a single gene from a specialized telomeric expression site at any time (4, 5). The parasite population collectively express multiple VSG; when the host becomes immune to the prevailing VSG, clones expressing alternative copies proliferate in a frequency-dependent manner, maintaining the infection and resulting in characteristic “waves of parasitaemia.” To survive long-term, T. brucei must generate novel VSG sequences through recombination; mechanisms may include domain shuffling (7) and gene conversion among silent, subtelomeric gene copies or possibly in situ within the expression site (8). Functional variant antigens in T. brucei consist of a- and b-type VSG (hereafter a-VSG and b-VSG), which share the cysteine-rich C-terminal domain (CTD) but are otherwise distantly related (9⇓–11). Although VSG are known to occur in T. congolense and T. vivax (12⇓⇓⇓–16), the repertoire of variant antigens in these species is uncharacterized. Consequently, the evolutionary diversification of the VSG gene family has not been examined, although it has been suggested that VSG are a source of novel genes. Two gene families, the expression site-associated genes (ESAG6/7) encoding transferrin receptor (TFR) and the VSG-related (VR) genes, are thought to have evolved from a-VSG (17, 18) and b-VSG (8, 11), respectively.

The antigenic variation phenotype is observed in all African trypanosomes, and it is assumed that this reflects a common physiological model, which has been defined in T. brucei. The aim of this study is to identify the evolutionary processes that have created contemporary VSG diversity and reveal any significant differences in how trypanosome species generate variant antigens. Despite their shared phenotype, our results show that species differ in the organization of antigenic diversity at the genome level, and they provide a basis to better understand disease progression, pathology, and host range in all African trypanosomes.
Original languageEnglish
Pages (from-to)3416-3421
Number of pages6
JournalProceedings of the National Academy of Sciences of the United States of America
Issue number9
Publication statusPublished - 28 Feb 2012


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