Antigenic diversity is generated by distinct evolutionary mechanisms in African trypanosome species
Antigenic diversity is generated by distinct evolutionary mechanisms in African trypanosome species
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DOI：
10.1073/pnas.1117313109
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发表时间：
2012-02-28
影响因子：
11.1
通讯作者：
Berriman, Matthew
中科院分区：
文献类型：
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作者：
Jackson, Andrew P.;Berry, Andrew;Berriman, Matthew
抗原变异使病原体能够通过表面蛋白的不断转换来避免宿主免疫反应。原生动物血液寄生虫布氏锥虫会导致撒哈拉以南非洲地区的人类非洲锥虫病（“昏睡病”），它是抗原变异的模型系统，通过定期更换覆盖其细胞表面的单层变异表面糖蛋白 (VSG) 来生存。我们将布氏锥虫与两种密切相关的寄生虫刚果锥虫和间日锥虫的基因组进行了比较，以揭示变异抗原库是如何进化的以及它如何影响当代抗原多样性。我们重建了 VSG 多样化，表明刚果锥虫使用源自多个祖先 VSG 谱系的变异抗原，而布氏锥虫 VSG 具有最近的起源，并且祖先基因谱系已被反复选择为新功能。这些历史差异反映在物种之间重组规模和机制上的根本差异上。使用系统发育不相容性作为遗传交换的指标，我们发现刚果锥虫和布氏锥虫之间的重组频率相当，但间日锥虫的重组频率要低得多。此外，在表明布氏锥虫 VSG 的 C 末端结构域在促进交换中起着至关重要的作用时，我们揭示了 VSG 多样化机制中的重大物种差异。我们的结果证明了过去的 VSG 进化如何间接决定当代寄生虫通过重组产生新变异抗原的能力，并表明目前布氏锥虫抗原变异的模型只是这些寄生虫维持慢性感染的一种手段。
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.