How Does the VSG Coat of Bloodstream Form African Trypanosomes Interact with External Proteins?
How Does the VSG Coat of Bloodstream Form African Trypanosomes Interact with External Proteins?
复制标题
VSG的血液涂层如何形成非洲锥虫体与外部蛋白质相互作用？
DOI：
10.1371/journal.ppat.1005259
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发表时间：
2015-12
期刊：
影响因子：
6.7
通讯作者：
Carrington M
中科院分区：
文献类型：
--
作者：
Schwede A;Macleod OJ;MacGregor P;Carrington M
关于“覆盖哺乳动物血流形式布氏锥虫外部表面的变异表面糖蛋白（VSG）涂层作为物理屏障”的说法经常出现在研究文章和评论中。不可穿透的VSG外套的概念是一个有吸引力的，因为它提供了一个清晰的模型来理解锥虫种群如何持续存在;每个连续的VSG保护质膜，并且在免疫学上与以前的VSG不同。有什么证据表明VSG外套是一个不可穿透的屏障，抗体和其他细胞外蛋白如何与它相互作用？在这篇综述中，描述了血液形式锥虫的细胞外表面的性质，并使用VSG序列和结构的知识进行分析，当实验进行时，过去的实验，调查抗体和凝集素与锥虫的结合。一些VSG单克隆抗体的表位尽可能地从先前的实验数据映射到VSG结构的模型上。结合凝集素的一些，但不是其他的，VSGs重新与最近的知识的位置和性质的N-连接的寡糖。结论是：（i）在早期实验中观察到的许多变化可以通过单个VSG的身份来解释。(ii)单个VSG的大部分可接近抗体，并且阻止接近细胞表面的屏障可能位于VSG N-末端结构域的基部，距离质膜约5 nm。这第二个结论突出了我们对VSG外壳如何工作的理解中的差距，因为具有大胞外结构域的几种质膜蛋白不太可能被VSG隐藏在宿主抗体中。非洲锥虫已经进化出两种关键策略来防止宿主免疫反应的杀伤，从而在哺乳动物中保持长期感染。两者都基于单一蛋白质的密集包装的外壳，即变体表面糖蛋白（VSG），其覆盖细胞的整个细胞外表面。第一种策略是抗原变异，通过这种策略，单个细胞以低频率转换表达的VSG的身份，并被宿主免疫应答选择。如果VSG是新的，锥虫增殖，维持感染;如果它不转换，或者如果新的VSG不是新的，它将被杀死。在第二种策略中，VSG充当保护屏障，保护细胞免受先天性和适应性免疫因子的影响，直到有压倒性滴度的抗体识别所表达的VSG。在这篇综述中，VSG外套的建模，和过去的实验，研究它如何保护锥虫使用目前的知识VSG序列和结构进行了重新审视。结论如下：（i）单个VSG的身份解释了早期实验变异;（ii）大多数VSG分子可被抗体接近。这第二个结论突出了我们对VSG外壳如何工作的理解中的差距，因为具有大胞外结构域的几种质膜蛋白不太可能被VSG隐藏在宿主抗体中。
Variations on the statement “the variant surface glycoprotein (VSG) coat that covers the external face of the mammalian bloodstream form of Trypanosoma brucei acts a physical barrier” appear regularly in research articles and reviews. The concept of the impenetrable VSG coat is an attractive one, as it provides a clear model for understanding how a trypanosome population persists; each successive VSG protects the plasma membrane and is immunologically distinct from previous VSGs. What is the evidence that the VSG coat is an impenetrable barrier, and how do antibodies and other extracellular proteins interact with it? In this review, the nature of the extracellular surface of the bloodstream form trypanosome is described, and past experiments that investigated binding of antibodies and lectins to trypanosomes are analysed using knowledge of VSG sequence and structure that was unavailable when the experiments were performed. Epitopes for some VSG monoclonal antibodies are mapped as far as possible from previous experimental data, onto models of VSG structures. The binding of lectins to some, but not to other, VSGs is revisited with more recent knowledge of the location and nature of N-linked oligosaccharides. The conclusions are: (i) Much of the variation observed in earlier experiments can be explained by the identity of the individual VSGs. (ii) Much of an individual VSG is accessible to antibodies, and the barrier that prevents access to the cell surface is probably at the base of the VSG N-terminal domain, approximately 5 nm from the plasma membrane. This second conclusion highlights a gap in our understanding of how the VSG coat works, as several plasma membrane proteins with large extracellular domains are very unlikely to be hidden from host antibodies by VSG. African trypanosomes have evolved two key strategies to prevent killing by the host immune response and, thus, maintain a long-term infection in a mammal. Both are based on a densely packed coat of a single protein, the variant surface glycoprotein (VSG), which covers the entire extracellular surface of the cell. The first strategy is antigenic variation, through which individual cells switch the identity of the expressed VSG at a low frequency and are selected by the host immune response. If the VSG is novel, the trypanosome proliferates, maintaining the infection; if it doesn't switch, or if the new VSG is not novel, it will be killed. In the second strategy, the VSG acts as a protective barrier, shielding the cell from innate and adaptive immune factors until there is an overwhelming titre of antibodies recognising the expressed VSG. In this review, the VSG coat is modelled, and past experiments that investigated how it protected the trypanosome are revisited using current knowledge of VSG sequence and structure. The conclusions are: (i) the identity of the individual VSGs explains early experimental variation; (ii) most of the VSG molecule is accessible to antibodies. This second conclusion highlights a gap in our understanding of how the VSG coat works, as several plasma membrane proteins with large extracellular domains are very unlikely to be hidden from host antibodies by VSG.