恶性疟原虫许多人熟悉的是导致最严重的疟疾形式的寄生虫。疟疾每年造成约2亿感染，至少有50万人死亡，后者的大部分是5岁以下的儿童，其中感染如此严重的原因之一就是寄生虫在血管中隔离的能力并逃避其宿主的免疫反应，继续在敌对的内部环境中繁殖。

关键的生存因素疟原虫在其人类宿主中是蛋白质PFEMP1（恶性疟原虫红细胞膜蛋白1）。这被导出到感染的红细胞表面，导致它们粘附在血管的内皮衬里，并防止其运输到脾脏并随后的破坏（以及搭便车的寄生虫）。不幸的是，隔离的红细胞（尤其是在大脑中）会阻碍血管，导致出血和缺氧等并发症，并导致疾病最严重的脑疟疾表现。

PFEMP1对寄生虫生存的重要性使其成为免疫系统的关键目标。

然而，疟原虫has evolved a way to evade the immune response by producing and switching between different PfEMP1 variants. Thus when one variant is targeted by the immune system a different variant – not yet recognised – becomes the dominant expressed form and allows the infection to persist.

PFEMP1蛋白由一个称为的大型多基因家族编码varcomprising ~60 different genes each producing an alternative PfEMP1. Recombination processes in these genes also allow for the creation of new variants, granting the parasite many millions of potential PfEMP1s.

The relationship betweenvarexpression and antigenic variation of PfEMP1 is well-established but the processes which govern switching and ensure expression of only a single variant at any one time are less well understood. In general it is thought thatvargene expression is governed by epigenetic mechanisms; that is to say by factors markingvar- 编码染色质并导致基因被遗传性打开或关闭。例如，acetylation and methylation state of histonescan dictate whether individualvar基因是“ OFF”或“ ON”的，也可能有一个专用的”permissive site’在核中只有一个var基因可能一次占据。关于这一研究领域的完整评论疟原虫可以被找寻到here。

张最近的论文et al通过描述以前未知的表达控制过程来促进进一步的可能性vargene RNA transcripts. Zhang and colleagues used bioinformatic methods to identify a novel exoribonuclease called PfRNase II. This protein appeared not to belong to the complex that controls standard RNA processing, maintenance and degradation (called the exosome) but it did degrade single-stranded RNA, validating it as an RNase.

研究者无法把PfRNase我I without affecting parasite survival, and inferred that the gene therefore had an essential function. Instead, they employed an alternative method that allowed them to temporarily degrade the protein without inactivating the endogenous gene. By fusing a destabilization domain (FK506-binding protein, FKBP) to the end of PfRNase II, the researchers could control whether or not the protein was degraded by adding or withholding a protective ligand. In fact, the tagged protein maintained only some of its usual functions, allowing these parasites to survive, but without their normal control overvargene expression patterns (the addition of a large tag can often in itself disrupt an enzyme’s normal function).

然后，研究人员使用该系统来研究具有活性或无效PFRNase II的转录模式。RNase灭活的寄生虫实质上上调了213个基因，几乎所有基因来自变异的毒力基因家族（例如，var）或来自相邻的基因组区域。还有一个特定的联系var被称为UPSAwhich were very highly upregulated, despite being rarely expressedin vitro。

UPSA varS特别有趣，因为它们的表达与该领域最严重的疟疾表现有关。确实，张et al.analysed transcript levels from patients and found, as previously reported, that levels ofUPSAtranscripts were higher in patients with severe as opposed to uncomplicated disease. Importantly, this correlated with low levels of PfRNase II expression, suggesting that low levels of RNase activity may directly promote the switching on of severe-disease-associated antigens.

最重要的是，没有PFRNase II活性的寄生虫失去了仅表达单个的能力vargene at a time, with several variants from bothUPSAandUPSC亚组共表达。这表明PFRNase II负责沉默vargenes by constantly degrading RNA transcripts and, by extension, thatvar基因不断产生短寿命的转录本 - 这种状态可能会为快速抗原开关的寄生虫提供启示。这与较早的观察结果相符UPSA vargenes are the most ‘labile’ of thevarfamily –病人很容易打开但是也switching off readilyin vitro。A key question for the future will be what controls the controller: does the level of PfRNase II vary at random during human infections, or might it be responsive to the human host environment?

最后，该机制也可能适用于单独表达一种变异抗原之一的其他寄生虫，这是许多原生动物寄生虫的共同特征贾迪亚and锥虫瘤；or indeed any other organism which employs single expression from a panel of multiple variants. It will be fascinating to discover how widespread and conserved such a mechanism might be. As to prospects for improved treatment of malaria, PfRNase II may prove to be a valuable tool to manipulate the expression of parasite virulence genes or indeed – since it is essential for parasite survival – an important new target for therapy in its own right.