A systems-based analysis of Plasmodium vivax lifecycle transcription from human to mosquito.
A systems-based analysis of Plasmodium vivax lifecycle transcription from human to mosquito.
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DOI：
10.1371/journal.pntd.0000653
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发表时间：
2010-04-06
影响因子：
3.8
通讯作者：
Winzeler EA
中科院分区：
文献类型：
--
作者：
Westenberger SJ;McClean CM;Chattopadhyay R;Dharia NV;Carlton JM;Barnwell JW;Collins WE;Hoffman SL;Zhou Y;Vinetz JM;Winzeler EA
多达40%的世界人口面临着间日疟的风险，这种疾病给流行国家带来了重大的公共卫生和经济负担。由于间日疟原虫产生潜伏的肝脏形态，根除间日疟原虫比根除恶性疟原虫更具挑战性。由于体外培养的局限性，间日疟原虫的遗传分析异常困难。为了克服间日疟原虫传统分子生物学的障碍，我们检测了感染患者和蚊子样本中寄生虫转录的变化，以确定基因功能，定义调控序列，并揭示新的潜在疫苗候选基因。我们观察到在不同的生命周期阶段，不同基因的转录水平发生了戏剧性的变化，表明发育是通过调节mRNA水平来部分调控的。我们的数据显示，参与常见生物过程或分子机制的基因是共表达的。我们鉴定了共表达基因上游的DNA序列基序，这些基序在疟原虫物种中是保守的，可能是调节阶段特异转录的蛋白质的结合位点。我们发现，尽管间日疟原虫子孢子具有形成催产素的能力，但在其他疟原虫物种中，它们表现出与肝细胞入侵和肝脏发育所需的相同基因的阶段特异性表达。我们发现，许多预测的输出蛋白和多基因家族成员也显示出高度协调的转录。我们的结论是，高质量的基因表达数据可以很容易地直接从患者样本中获得，并且在不同的间日疟原虫生命周期阶段上调的许多相同的未表征基因在其他疟原虫物种中也在类似的阶段上调。我们还提供了许多例子，说明系统生物学是如何成为确定由于实验困难而被忽视的病原体中基因可能功能的一种有效方法。在非洲以外的2.5亿疟疾病例中，大多数是由间日疟原虫引起的。虽然药物可以用来治疗间日疟，但耐药性正在蔓延，而且还没有可用的疫苗。因为这个物种不能在实验室中容易地生长，所以理解基因组中许多假想基因的功能是额外的挑战。我们从生长在人类血液和蚊子中的寄生虫中分离出转录信息，标记这些信息，并测量它们在不同寄生虫生长条件下的水平。5419个寄生虫基因的数据显示，随着寄生虫在人和蚊子之间移动，这些基因发生了广泛的变化，并揭示了高表达的基因，其蛋白可能代表实验疫苗的新治疗靶点。我们发现了一组基因，这些基因可能在肝细胞感染的早期阶段发挥作用。我们发现不同血液期寄生虫的表达模式存在有趣的差异，这可能与宿主的反应状态有关。
Up to 40% of the world's population is at risk for Plasmodium vivax malaria, a disease that imposes a major public health and economic burden on endemic countries. Because P. vivax produces latent liver forms, eradication of P. vivax malaria is more challenging than it is for P. falciparum. Genetic analysis of P. vivax is exceptionally difficult due to limitations of in vitro culture. To overcome the barriers to traditional molecular biology in P. vivax, we examined parasite transcriptional changes in samples from infected patients and mosquitoes in order to characterize gene function, define regulatory sequences and reveal new potential vaccine candidate genes. We observed dramatic changes in transcript levels for various genes at different lifecycle stages, indicating that development is partially regulated through modulation of mRNA levels. Our data show that genes involved in common biological processes or molecular machinery are co-expressed. We identified DNA sequence motifs upstream of co-expressed genes that are conserved across Plasmodium species that are likely binding sites of proteins that regulate stage-specific transcription. Despite their capacity to form hypnozoites we found that P. vivax sporozoites show stage-specific expression of the same genes needed for hepatocyte invasion and liver stage development in other Plasmodium species. We show that many of the predicted exported proteins and members of multigene families show highly coordinated transcription as well. We conclude that high-quality gene expression data can be readily obtained directly from patient samples and that many of the same uncharacterized genes that are upregulated in different P. vivax lifecycle stages are also upregulated in similar stages in other Plasmodium species. We also provide numerous examples of how systems biology is a powerful method for determining the likely function of genes in pathogens that are neglected due to experimental intractability. Most of the 250 million malaria cases outside of Africa are caused by the parasite Plasmodium vivax. Although drugs can be used to treat P. vivax malaria, drug resistance is spreading and there is no available vaccine. Because this species cannot be readily grown in the laboratory there are added challenges to understanding the function of the many hypothetical genes in the genome. We isolated transcriptional messages from parasites growing in human blood and in mosquitoes, labeled the messages and measured how their levels for different parasite growth conditions. The data for 5,419 parasite genes shows extensive changes as the parasite moves between human and mosquito and reveals highly expressed genes whose proteins might represent new therapeutic targets for experimental vaccines. We discover sets of genes that are likely to play a role in the earliest stages of hepatocyte infection. We find intriguing differences in the expression patterns of different blood stage parasites that may be related to host-response status.
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影响因子：
12.3
作者：
Dharia NV;Sidhu AB;Cassera MB;Westenberger SJ;Bopp SE;Eastman RT;Plouffe D;Batalov S;Park DJ;Volkman SK;Wirth DF;Zhou Y;Fidock DA;Winzeler EA
通讯作者：
Winzeler EA
影响因子：
9.8
作者：
Bozdech, Zbynek;Llinas, Manuel;Pulliam, Brian Lee;Wong, Edith D;Zhu, Jingchun;DeRisi, Joseph L
通讯作者：
DeRisi, Joseph L
影响因子：
64.8
作者：
Carlton, Jane M.;Adams, John H.;Silva, Joana C.;Bidwell, Shelby L.;Lorenzi, Hernan;Caler, Elisabet;Crabtree, Jonathan;Angiuoli, Samuel V.;Merino, Emilio F.;Amedeo, Paolo;Cheng, Qin;Coulson, Richard M. R.;Crabb, Brendan S.;del Portillo, Hernando A.;Essien, Kobby;Feldblyum, Tamara V.;Fernandez-Becerra, Carmen;Gilson, Paul R.;Gueye, Amy H.;Guo, Xiang;Kang'a, Simon;Kooij, Taco W. A.;Korsinczky, Michael;Meyer, Esmeralda V. -S.;Nene, Vish;Paulsen, Ian;White, Owen;Ralph, Stuart A.;Ren, Qinghu;Sargeant, Tobias J.;Salzberg, Steven L.;Stoeckert, Christian J.;Sullivan, Steven A.;Yamamoto, Marcio M.;Hoffman, Stephen L.;Wortman, Jennifer R.;Gardner, Malcolm J.;Galinski, Mary R.;Barnwell, John W.;Fraser-Liggett, Claire M.
通讯作者：
Fraser-Liggett, Claire M.
影响因子：
4.8
作者：
Bradley, PJ;Ward, C;Boothroyd, JC
通讯作者：
Boothroyd, JC
影响因子：
--
作者：
Gilk, Stacey D.;Raviv, Yossef;Ward, Gary E.
通讯作者：
Ward, Gary E.