Laboratório Especial de Ciclo Celular, Center of Toxins, Immune Response and Cell Signaling (CeTICS), Instituto Butantan, São Paulo, Brazil.
The Wellcome Centre for Molecular Parasitology, Institute of Infection, Immunity and Inflammation, University of Glasgow, Glasgow, United Kingdom.
PLoS Pathog. 2018 Nov 15;14(11):e1007321. doi: 10.1371/journal.ppat.1007321. eCollection 2018 Nov.
Antigenic variation by variant surface glycoprotein (VSG) coat switching in African trypanosomes is one of the most elaborate immune evasion strategies found among pathogens. Changes in the identity of the transcribed VSG gene, which is always flanked by 70-bp and telomeric repeats, can be achieved either by transcriptional or DNA recombination mechanisms. The major route of VSG switching is DNA recombination, which occurs in the bloodstream VSG expression site (ES), a multigenic site transcribed by RNA polymerase I. Recombinogenic VSG switching is frequently catalyzed by homologous recombination (HR), a reaction normally triggered by DNA breaks. However, a clear understanding of how such breaks arise-including whether there is a dedicated and ES-focused mechanism-is lacking. Here, we synthesize data emerging from recent studies that have proposed a range of mechanisms that could generate these breaks: action of a nuclease or nucleases; repetitive DNA, most notably the 70-bp repeats, providing an intra-ES source of instability; DNA breaks derived from the VSG-adjacent telomere; DNA breaks arising from high transcription levels at the active ES; and DNA lesions arising from replication-transcription conflicts in the ES. We discuss the evidence that underpins these switch-initiation models and consider what features and mechanisms might be shared or might allow the models to be tested further. Evaluation of all these models highlights that we still have much to learn about the earliest acting step in VSG switching, which may have the greatest potential for therapeutic intervention in order to undermine the key reaction used by trypanosomes for their survival and propagation in the mammalian host.
在非洲锥虫中,通过变异表面糖蛋白 (VSG) 外套的转换实现抗原变异是病原体中发现的最复杂的免疫逃避策略之一。转录的 VSG 基因的身份变化,该基因总是被 70bp 和端粒重复序列侧翼,可以通过转录或 DNA 重组机制来实现。VSG 转换的主要途径是 DNA 重组,它发生在血流 VSG 表达位点 (ES) 中,这是一个由 RNA 聚合酶 I 转录的多基因位点。重组性 VSG 转换通常由同源重组 (HR) 催化,这是一种由 DNA 断裂引发的反应。然而,对于这些断裂是如何产生的,包括是否存在专门的 ES 聚焦机制,人们还没有清晰的认识。在这里,我们综合了最近的研究数据,这些研究提出了一系列可能产生这些断裂的机制:核酸酶或核酸酶的作用;重复 DNA,尤其是 70bp 重复序列,为 ES 内的不稳定性提供了一个来源;来自 VSG 相邻端粒的 DNA 断裂;来自活性 ES 中高转录水平的 DNA 断裂;以及在 ES 中复制转录冲突产生的 DNA 损伤。我们讨论了支持这些开关起始模型的证据,并考虑了哪些特征和机制可能共享或允许进一步测试这些模型。评估所有这些模型都强调,我们仍然需要了解 VSG 转换中最早作用的步骤,这可能为治疗干预提供最大的潜力,以破坏锥虫在哺乳动物宿主中生存和繁殖所使用的关键反应。