Anti-schistosomal intervention targets identified by lifecycle transcriptomic analyses.
Anti-schistosomal intervention targets identified by lifecycle transcriptomic analyses.
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DOI：
10.1371/journal.pntd.0000543
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发表时间：
2009-11-03
影响因子：
3.8
通讯作者：
Hoffmann KF
中科院分区：
文献类型：
--
作者：
Fitzpatrick JM;Peak E;Perally S;Chalmers IW;Barrett J;Yoshino TP;Ivens AC;Hoffmann KF
迫切需要新的方法来确定驱虫药物和疫苗的目标，特别是对于那些寄生虫物种目前正在控制的单一，往往是有限的策略。更清楚地了解蠕虫发展的基础上的转录成分，将能够识别成功的寄生虫/宿主相互作用所必需的可利用的分子。为此，我们提出了一个组合，生物信息学为主导的方法，采用统计和网络分析的转录组数据，确定新的免疫预防和治疗铅目标，以打击血吸虫病。利用由37，632个元件组成的曼氏血吸虫寡核苷酸DNA微阵列，能够从15个不同的寄生虫生命周期阶段进行基因表达谱分析，跨越三个独特的生态位。数据分析的统计方法揭示了973个基因产物的差异表达，最低限度地描述了三个主要特征的寄生虫发展：无性过程中的中间蜗牛主机，性成熟内确定的脊椎动物主机和性二型性成年男性和女性蠕虫。此外，我们确定了一组338个组成型表达的染色体基因产物（包括41个转录本，在扁形动物之外没有序列相似性），这可能是染色体生命周期进展所必需的。虽然信息量很大，但以生物信息学为主导的转录数据集的生物信息学挖掘具有局限性，包括无法识别差异表达的转录本和生命周期阶段之间的高阶关系。网络分析，再加上基因本体富集调查，促进了数据集的重新检查，并确定了387个集群（包含12,132个基因产物），展示了发育调节类的新例子（包括294个在扁形动物之外没有已知序列相似性的童虫和/或成体转录本），这些都是统计比较无法检测到的。总的来说，对转录组数据集的统计和基于网络的探索性分析已经导致了对异常发育的彻底表征。从这些实验中获得的信息突出了与生命周期进展相关的关键转录程序，并鉴定了许多抗溶酶体候选分子，包括G蛋白偶联受体、四跨膜蛋白、Dyn型过氧化物酶、岩藻糖基转移酶、利什曼溶血素和netrin/netrin受体复合物。尽管在过去十年中实施了重点突出和资金充足的化疗控制举措，但血吸虫病仍然是发展中国家发病率和死亡率的重要原因。因此，迫切需要将基因组信息迅速转化为可行的疫苗或新的药物类别，能够根除导致这一被忽视的热带疾病的寄生性寄生蠕虫。在我们的努力，以确定新的化疗和免疫预防干预的潜在目标，我们详细介绍了一个组合的生物信息学方法，包括探索性的统计和网络分析，彻底描述了曼氏血吸虫在三个环境小生境的转录进展。我们的研究结果表明，虽然寄生虫是主机欺骗和生存的主人，有许多可利用的候选分子显示在整个寄生虫的生命周期的差异或组成型表达。重要的是，这些转录本中的一些代表了在扁形动物门外不常见或在扁形动物门内不常见的基因家族，因此代表了优先目标。本文确定的许多候选人将受到正在进行的和未来的假设为主导的功能调查。完成这些具体的检查最终将有助于成功开发新的控制策略，用于减轻染色体诱导的免疫病理学，发病率和死亡率。
Novel methods to identify anthelmintic drug and vaccine targets are urgently needed, especially for those parasite species currently being controlled by singular, often limited strategies. A clearer understanding of the transcriptional components underpinning helminth development will enable identification of exploitable molecules essential for successful parasite/host interactions. Towards this end, we present a combinatorial, bioinformatics-led approach, employing both statistical and network analyses of transcriptomic data, for identifying new immunoprophylactic and therapeutic lead targets to combat schistosomiasis. Utilisation of a Schistosoma mansoni oligonucleotide DNA microarray consisting of 37,632 elements enabled gene expression profiling from 15 distinct parasite lifecycle stages, spanning three unique ecological niches. Statistical approaches of data analysis revealed differential expression of 973 gene products that minimally describe the three major characteristics of schistosome development: asexual processes within intermediate snail hosts, sexual maturation within definitive vertebrate hosts and sexual dimorphism amongst adult male and female worms. Furthermore, we identified a group of 338 constitutively expressed schistosome gene products (including 41 transcripts sharing no sequence similarity outside the Platyhelminthes), which are likely to be essential for schistosome lifecycle progression. While highly informative, statistics-led bioinformatics mining of the transcriptional dataset has limitations, including the inability to identify higher order relationships between differentially expressed transcripts and lifecycle stages. Network analysis, coupled to Gene Ontology enrichment investigations, facilitated a re-examination of the dataset and identified 387 clusters (containing 12,132 gene products) displaying novel examples of developmentally regulated classes (including 294 schistosomula and/or adult transcripts with no known sequence similarity outside the Platyhelminthes), which were undetectable by the statistical comparisons. Collectively, statistical and network-based exploratory analyses of transcriptomic datasets have led to a thorough characterisation of schistosome development. Information obtained from these experiments highlighted key transcriptional programs associated with lifecycle progression and identified numerous anti-schistosomal candidate molecules including G-protein coupled receptors, tetraspanins, Dyp-type peroxidases, fucosyltransferases, leishmanolysins and the netrin/netrin receptor complex. Despite the implementation of focused and well-funded chemotherapeutic control initiatives over the last decade, schistosomiasis remains a significant cause of morbidity and mortality within countries of the developing world. There is, therefore, an urgent need for the rapid translation of genomic information into viable vaccines or new drug classes capable of eradicating the parasitic schistosome worms responsible for this neglected tropical disease. In our effort to identify potential targets for novel chemotherapeutic and immunoprophylactic interventions, we detail a combined bioinformatics approach, comprising exploratory statistical and network analyses, to thoroughly describe the transcriptional progression of Schistosoma mansoni across three environmental niches. Our results indicate that, although schistosomes are masters at host deception and survival, there are numerous exploitable candidate molecules displaying either differential or constitutive expression throughout the parasite's lifecycle. Importantly, some of these transcripts represent gene families not commonly found outside—or expanded within—the phylum Platyhelminthes, and thus represent priority targets. Many of the candidates identified herein will be subjected to ongoing and future hypothesis-led functional investigations. The completion of such specific examinations ultimately will contribute to the successful development of novel control strategies useful in the alleviation of schistosome-induced immunopathologies, morbidities and mortalities.
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影响因子：
4.8
作者：
Fitzpatrick, Jennifer M.;Hirai, Yuriko;Hoffmann, Karl F.
通讯作者：
Hoffmann, Karl F.
影响因子：
3.6
作者：
Fredriksson, R;Schiöth, HB
通讯作者：
Schiöth, HB
影响因子：
2.1
作者：
CREWSOYEN, AE;YOSHINO, TP
通讯作者：
YOSHINO, TP
影响因子：
3.7
作者：
Caffrey CR;Rohwer A;Oellien F;Marhöfer RJ;Braschi S;Oliveira G;McKerrow JH;Selzer PM
通讯作者：
Selzer PM
影响因子：
14.9
作者：
Finn RD;Mistry J;Tate J;Coggill P;Heger A;Pollington JE;Gavin OL;Gunasekaran P;Ceric G;Forslund K;Holm L;Sonnhammer EL;Eddy SR;Bateman A
通讯作者：
Bateman A