A Host-Pathogen Interaction Reduced to First Principles: Antigenic Variation in T. brucei
A Host-Pathogen Interaction Reduced to First Principles: Antigenic Variation in T. brucei
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DOI：
10.1007/978-3-319-20819-0_2
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发表时间：
2015-01-01
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影响因子：
--
通讯作者：
Schulz, Danae
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作者：
Hovel-Miner, Galadriel;Mugnier, Monica;Schulz, Danae
抗原变异是一种常见的微生物生存策略，由感染过程中整个病原体群体表达的表面抗原的多样性提供动力。即便如此，在病原体中，非洲锥虫具有所描述的最全面的抗原变异系统。非洲锥虫（布氏锥虫）是原产于撒哈拉以南非洲的单细胞寄生虫，是人类昏睡病和牲畜n'agana的病原体。它们在两个栖息地之间循环：一种特定的苍蝇（Glossina spp.）。或通俗地说，采采蝇）和它们的哺乳动物宿主的血液，通过呈现一系列增殖和静止的发育形式，这些形式在细胞结构和功能上变化很大。在这些转变过程中出现的每一种发育形式的关键是覆盖质膜的表面涂层的组成。锥虫表面涂层非常致密，由数百万个发育特异性蛋白质的重复序列覆盖：前环蛋白基因产物在舌蝇体内覆盖生物体，而后环蛋白基因产物在苍蝇唾液腺中覆盖生物体，准备好进入哺乳动物的血液循环。但到目前为止，最有趣的外壳是变异表面糖蛋白（VSG）外壳，它覆盖着感染形式的生物体（在此期间，它必须在哺乳动物的血液中自由生存）。这种外壳是高度抗原性的，并且是非常稳健的VSG特异性抗体，其介导有效的调理作用和补体介导的寄生虫的裂解，寄生虫携带针对其作出应答的外壳。与此同时，一小部分寄生虫种群交换外套，这刺激了对流行的（新的）VSG物种的新抗体反应，并且这个过程重复直到免疫系统失败。这种疾病是致命的，除非治疗，治疗在后期是非常有毒的。因为有机体是自由生活在血液中，VSG：抗体表面代表病原体和宿主之间的界面，并定义了寄生虫与免疫反应的相互作用。这种相互作用（VSG转换，抗体产生和寄生虫删除的循环）导致了100多年前首次认识到的寄生虫血症的刻板高峰和低谷。从本质上讲，T.布氏病是由于在群体水平上需要维持广泛的库以逃避抗体应答。在本章中，我们将研究目前已知的VSG库，它的深度，以及在分子（DNA）和表型（表面显示）水平上使其多样化的机制，以及它如何与宿主中特异性针对它的抗体相互作用。
Antigenic variation is a common microbial survival strategy, powered by diversity in expressed surface antigens across the pathogen population over the course of infection. Even so, among pathogens, African trypanosomes have the most comprehensive system of antigenic variation described. African trypanosomes (Trypanosoma brucei spp.) are unicellular parasites native to sub-Saharan Africa, and the causative agents of sleeping sickness in humans and of n'agana in livestock. They cycle between two habitats: a specific species of fly (Glossina spp. or, colloquially, the tsetse) and the bloodstream of their mammalian hosts, by assuming a succession of proliferative and quiescent developmental forms, which vary widely in cell architecture and function. Key to each of the developmental forms that arise during these transitions is the composition of the surface coat that covers the plasma membrane.The trypanosome surface coat is extremely dense, covered by millions of repeats of developmentally specified proteins: procyclin gene products cover the organism while it resides in the tsetse and metacyclic gene products cover it while in the fly salivary glands, ready to make the transition to the mammalian bloodstream. But by far the most interesting coat is the Variant Surface Glycoprotein (VSG) coat that covers the organism in its infectious form (during which it must survive free living in the mammalian bloodstream). This coat is highly antigenic and elicits robust VSG-specific antibodies that mediate efficient opsonization and complement mediated lysis of the parasites carrying the coat against which the response was made. Meanwhile, a small proportion of the parasite population switches coats, which stimulates a new antibody response to the prevalent (new) VSG species and this process repeats until immune system failure. The disease is fatal unless treated, and treatment at the later stages is extremely toxic.Because the organism is free living in the blood, the VSG: antibody surface represents the interface between pathogen and host, and defines the interaction of the parasite with the immune response. This interaction (cycles of VSG switching, antibody generation, and parasite deletion) results in stereotypical peaks and troughs of parasitemia that were first recognized more than 100 years ago. Essentially, the mechanism of antigenic variation in T. brucei results from a need, at the population level, to maintain an extensive repertoire, to evade the antibody response. In this chapter, we will examine what is currently known about the VSG repertoire, its depth, and the mechanisms that diversify it both at the molecular (DNA) and at the phenotypic (surface displayed) level, as well as how it could interact with antibodies raised specifically against it in the host.