Department of Ecology and Evolutionary Biology, University of Michigan, 2019 Kraus Nat, Sci, Bldg,, 830 North University Ave, Ann Arbor 48109-1048, Michigan, USA.
BMC Microbiol. 2013 Nov 6;13:244. doi: 10.1186/1471-2180-13-244.
The primary target of the human immune response to the malaria parasite Plasmodium falciparum, P. falciparum erythrocyte membrane protein 1 (PfEMP1), is encoded by the members of the hyper-diverse var gene family. The parasite exhibits antigenic variation via mutually exclusive expression (switching) of the ~60 var genes within its genome. It is thought that different variants exhibit different host endothelial binding preferences that in turn result in different manifestations of disease.
Var sequences comprise ancient sequence fragments, termed homology blocks (HBs), that recombine at exceedingly high rates. We use HBs to define distinct var types within a local population. We then reanalyze a dataset that contains clinical and var expression data to investigate whether the HBs allow for a description of sequence diversity corresponding to biological function, such that it improves our ability to predict disease phenotype from parasite genetics. We find that even a generic set of HBs, which are defined for a small number of non-local parasites: capture the majority of local sequence diversity; improve our ability to predict disease severity from parasite genetics; and reveal a previously hypothesized yet previously unobserved parasite genetic basis for two forms of severe disease. We find that the expression rates of some HBs correlate more strongly with severe disease phenotypes than the expression rates of classic var DBLα tag types, and principal components of HB expression rate profiles further improve genotype-phenotype models. More specifically, within the large Kenyan dataset that is the focus of this study, we observe that HB expression differs significantly for severe versus mild disease, and for rosetting versus impaired consciousness associated severe disease. The analysis of a second much smaller dataset from Mali suggests that these HB-phenotype associations are consistent across geographically distant populations, since we find evidence suggesting that the same HB-phenotype associations characterize this population as well.
The distinction between rosetting versus impaired consciousness associated var genes has not been described previously, and it could have important implications for monitoring, intervention and diagnosis. Moreover, our results have the potential to illuminate the molecular mechanisms underlying the complex spectrum of severe disease phenotypes associated with malaria--an important objective given that only about 1% of P. falciparum infections result in severe disease.
人体对疟原虫恶性疟原虫（Plasmodium falciparum）的免疫反应的主要目标是恶性疟原虫红细胞膜蛋白 1（PfEMP1），它由超多样化的 var 基因家族成员编码。寄生虫通过其基因组内约 60 个 var 基因的相互排斥表达（切换）来表现抗原变异。据认为，不同的变体表现出不同的宿主内皮结合偏好，进而导致不同的疾病表现。
var 序列包含古老的序列片段，称为同源块（HBs），它们以极高的速率重组。我们使用 HBs 在局部种群内定义不同的 var 类型。然后，我们重新分析了一个包含临床和 var 表达数据的数据集，以调查 HBs 是否允许描述与生物学功能相对应的序列多样性，从而提高我们从寄生虫遗传学预测疾病表型的能力。我们发现，即使是一组通用的 HBs，它们是为少数非本地寄生虫定义的：也能捕获大多数本地序列多样性；提高我们从寄生虫遗传学预测疾病严重程度的能力；并揭示了两种严重疾病的先前假设但以前未观察到的寄生虫遗传基础。我们发现，一些 HBs 的表达率与严重疾病表型的相关性强于经典 var DBLα 标签类型的表达率，并且 HB 表达率分布的主成分进一步改善了基因型-表型模型。更具体地说，在本研究重点关注的大型肯尼亚数据集中，我们观察到严重疾病与轻度疾病之间以及与意识障碍相关的严重疾病与环型红细胞形成之间的 HB 表达存在显著差异。来自马里的第二个小得多的数据集的分析表明，这些 HB-表型关联在地理上遥远的人群中是一致的，因为我们有证据表明，同样的 HB-表型关联也描述了该人群。
关于与环型红细胞形成相关的 var 基因与意识障碍相关的 var 基因之间的区别以前没有描述过，这对于监测、干预和诊断可能具有重要意义。此外，我们的结果有可能阐明与疟疾相关的严重疾病表型复杂谱背后的分子机制，鉴于只有约 1%的恶性疟原虫感染导致严重疾病，这是一个重要目标。
