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

Abstract

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 coopted 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.

The Selenocysteine tRNA Gene in Leishmania major Is Transcribed by both RNA Polymerase II and RNA Polymerase III

“…Analyses of the genomic databases of T. cruzi (CL Brener) (39), T. vivax (Y486), and T. congolense (IL-3000) (40) showed that the presence of two tRNA-Sec genes is conserved across the genus Trypanosoma (Fig. 1B).…”

Anti–trypanosomal effect of Peristrophe bicalyculata extract on Trypanosoma brucei brucei–infected rats

“…African animal typanosomiasis causes serious losses in Cattle, sheep, goats, pigs, horses and many other host animals [1] , thus reducing the source of animal protein [2] , and ultimately contributing to food insecurity in the region. The development of a vaccine for the treatment of the disease is becoming increasingly difficult due to the problem of antigenic variation [3] , hence the dependence on chemotherapeutic agents to control the disease.…”

DNA Recombination Strategies During Antigenic Variation in the African Trypanosome

“…Genomic analyses have challenged this assumption, revealing significant differences between the VSG archives in the three species (75,84). Whole genome comparisons revealed that in T. congolense there is no equivalent of the T. brucei a-VSG subfamily; in contrast, there are two b-VSG subfamilies and a much greater range of distinct C-terminal domains (15-20 CTD types, each of which are found to be associated with particular VSG subtypes, in contrast to the single CTD found in T. brucei).…”

“…It is clear that we have only just begun to examine the processes that shape and diversify the VSG archive, and do not fully understand the events that operate during replication, over the course of an infection and through the life cycle. Understanding this will determine the extent to which archives compare or diverge in extant trypanosome isolates (47,84). Just as importantly, we do not yet understand if and how these largely silent processes within the archive intersect with our growing understanding of how VSGs are recombined into the BES.…”