In vivo profiles in malaria are consistent with a novel physiological state.
In vivo profiles in malaria are consistent with a novel physiological state.
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疟疾的体内特征与新的生理状态一致。
DOI：
10.1073/pnas.0904478106
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发表时间：
2009
影响因子：
11.1
通讯作者：
Regev,Aviv
中科院分区：
文献类型：
--
作者：
Wirth,Dyann;Daily,Johanna;Winzeler,Elizabeth;Mesirov,JillP;Regev,Aviv
勒米厄等(1)描述了对我们体内恶性疟原虫患者样本的再分析（2），支持我们的许多结论（环的唯一存在，簇中缺乏明显的无性阶段，簇1和配子发生之间的关系）。然而，Lemieux et al. (1)将观察到的体内分布拟合为配子体和无性形式mRNA的混合物（参考文献1中的图2E），得出的结论是，离散的簇与不同比例的有性定型但表型上无法区分的寄生虫相一致，由参数α反映。这种解释在计算和生物学上都是有问题的。从计算的角度来看，其模型中的所有聚类1样本都具有非常相似、唯一且高的α值（0.6）。这意味着这些患者具有非常相似的配子母细胞分数，这是极不可能的情况。此外，仅在表型可观察到的配子母细胞的高比例下，才在体外获得了相当的α值（图参考文献1中的2E和S8）。研究中的患者样本均不具有高比例的配子体，并且在大多数患者中，显微镜根本未检测到配子体。即使在体内样品中的配子体污染率很高，也不能解释观察到的糖酵解相关基因表达降低20倍，而在许多其他不参与代谢的性发育基因中没有任何实质性表达差异。特别是，早期配子发生的几个标记物（参考文献3中的表1和图2）在Clus中没有显示任何一致的诱导模式。
Lemieux et al.(1) describe a reanalysis of our in vivo Plasmodium falciparum patient samples (2), supporting many of our conclusions (exclusive presence of rings, lack of distinct asexual phases in the clusters, a relation between Cluster 1 and gametogenesis). However, Lemieux et al.(1) fit the observed in vivo profiles as a mixture of gametocyte and asexual form mRNA (Fig. 2E in ref. 1), concluding that the discrete clusters are consistent with varying proportions of sexually committed but phenotypically indistinguishable parasites, reflected by the parameter α.This interpretation is problematic on both computational and biological grounds. From a computational perspective, all Cluster 1 samples in their model have very similar, unique, and high α values (0.6). This implies that these patients had a very similar fraction of gametocytes, a highly unlikely situation. Furthermore, comparable α values are obtained in vitro only at a high fraction of phenotypically observable gametocytes (Figs. 2E and S8 in ref. 1). None of the patient samples in the study had a high fraction of gametocytes and in most patients, gametocytes were not detected by microscopy at all. Even a high gametocyte contamination rate in an in vivo sample could not explain the observed 20-fold decrease in the expression of glycolysis-related genes without any substantial expression differences in many other sexual development genes that are not involved in metabolism. In particular, several markers of early gametogenesis (Table 1 and Fig. 2 in ref. 3) do not show any consistent induction pattern in Clus-