Analysis of novel in vivo derived Plasmodium falciparum transcriptional profiles

新型体内恶性疟原虫转录谱分析

• 批准号: 7888198
• 负责人: Johanna Patricia Daily
• 金额: $ 39.45万
• 依托单位: ALBERT EINSTEIN COLLEGE OF MEDICINE
• 依托单位国家: 美国
• 财政年份: 2008
• 资助国家: 美国
• 起止时间: 2008-07-15 至 2013-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7888198
• 关键词: Address; Bioinformatics; Biological; Biology; Blood specimen; Cessation of life; Child; Clinical; Clinical Research; Collaborations; Coma; Complex; Computational Biology; Computer Analysis; Data; Disease; Disease Outcome; Environment; Environmental Monitoring; Epidemiology; Functional disorder; Gene Expression; Gene Expression Profile; Genes; Genetic Transcription; Genome; Genomics; Goals; Growth; Host-Parasite Relations; Human; Immune response; In Situ; In Vitro; Individual; Infection; Integration Host Factors; Intervention; Kenya; Laboratories; Malaria; Medical; Metabolism; Methods; Mitochondria; Modeling; Molecular; Molecular Biology; Molecular Genetics; Oxidative Phosphorylation; Parasites; Pathogenesis; Patients; Physiological; Physiology; Plasmodium falciparum; Process; Reporting; Research; Saccharomyces cerevisiae; Sampling; Severities; Site; Staging; Starvation; Stress; Symptoms; Syndrome; System; Temperature; Testing; Variant; Work; Yeasts; asexual; base; biological adaptation to stress; clinically relevant; field study; flu; global health; in vitro Model; in vivo; novel; pathogen; public health relevance; response; skills

DESCRIPTION (provided by applicant): Infection with the malaria parasite Plasmodium falciparum leads to widely different clinical conditions in children - ranging from mild flu-like symptoms to coma and death. Despite the immense medical implications, the genetic and molecular basis of this diversity remains largely unknown. We hypothesize that parasites residing in the human host have needed to adapt to this specialized environment that varies in temperature, substrate and immune response. To characterize parasite biology we have utilized whole genome analysis of the parasite from fresh blood samples of infected patients. With this approach we have identified three biologic states of the parasite when it resides in the human host. One of these in vivo states correlates highly to the laboratory grown transcriptional profile, and now we have identified two novel states. The biological basis of these states can be interpreted by comparison with an extensive compendium of expression data in the yeast, Saccharomyces cerevisiae. The three states in vivo closely resemble (i) active growth based on glycolytic metabolism "the in vitro like state"; (ii) a starvation response accompanied by oxidative phosphorylation; and (iii) an environmental stress response. The results reveal a previously unknown physiological diversity in the in vivo biology of the malaria parasite, in particular, evidence for functional mitochondria in the asexual stage parasite, and point to in vivo and in vitro studies to determine how this variation may impact disease manifestations and treatment. This work highlights the importance of working with human samples to explore clinically relevant parasite biology. Through further clinical studies we propose to 1) identify the host factors that are associated with these novel biologic states 2) identify parasite biology that is specifically found in severe disease 3) test environmental responses of the parasite under controlled conditions using the in vitro model. We are developing a completely novel model for the host pathogen interaction in this parasite. The clinical studies inform the in vitro model and conversely, results of this model can then be tested prospectively in the clinical studies. Furthermore we have developed team of leaders in clinical malaria, computational biology and molecular biology to combine their skills to further our understanding of disease. The long term goal is to identify parasite biology that can be targeted to reduce individual and global health burden of Plasmodium falciparum. PUBLIC HEALTH RELEVANCE: Plasmodium falciparum causes infections in humans which range from asymptomatic to highly severe illness often leading to death. Why some patients have severe disease and others are completely well remains poorly understood, and this may be related to specialized parasite biology that occurs in humans. Through the use of genomics, we have identified completely new parasite biology when it resides in humans and this project will determine if this novel biology is related to differences in disease outcomes. This study brings together experts in computational biology and malaria epidemiology to develop clinically relevant models of parasite biology to inform disease interventions to reduce the impact of malaria infection on individual and global health.

描述（由申请人提供）：感染疟疾寄生虫恶性疟原虫导致儿童的临床症状差异很大-从轻微的流感样症状到昏迷和死亡。尽管存在巨大的医学意义，但这种多样性的遗传和分子基础在很大程度上仍然未知。我们假设寄生在人类宿主体内的寄生虫需要适应这种特殊的环境，这种环境在温度，底物和免疫反应方面都有所不同。为了表征寄生虫生物学，我们利用了来自感染患者的新鲜血液样本的寄生虫的全基因组分析。通过这种方法，我们已经确定了寄生虫在人类宿主中的三种生物学状态。其中一种体内状态与实验室生长的转录谱高度相关，现在我们已经确定了两种新的状态。这些状态的生物学基础可以通过与酵母（Saccharomyces cerevisiae）中广泛的表达数据纲要进行比较来解释。体内的三种状态非常类似于（i）基于糖酵解代谢的活性生长“体外样状态”;（ii）伴随氧化磷酸化的饥饿反应;和（iii）环境应激反应。结果揭示了疟疾寄生虫体内生物学中以前未知的生理多样性，特别是无性阶段寄生虫中功能性线粒体的证据，并指出体内和体外研究以确定这种变化如何影响疾病表现和治疗。这项工作强调了与人类样本合作以探索临床相关寄生虫生物学的重要性。通过进一步的临床研究，我们建议1）确定与这些新的生物学状态相关的宿主因素2）确定在严重疾病中特别发现的寄生虫生物学3）使用体外模型在受控条件下测试寄生虫的环境反应。我们正在开发一种全新的模型，在这种寄生虫的宿主病原体相互作用。临床研究为体外模型提供信息，相反，该模型的结果可以在临床研究中进行前瞻性测试。此外，我们还培养了临床疟疾、计算生物学和分子生物学方面的领导者团队，将他们的技能联合收割机结合起来，进一步加深我们对疾病的理解。长期目标是确定可以有针对性地减少恶性疟原虫的个人和全球健康负担的寄生虫生物学。公共卫生相关性：恶性疟原虫引起人类感染，其范围从无症状到高度严重的疾病，通常导致死亡。为什么有些患者患有严重疾病，而另一些患者则完全健康，人们对此知之甚少，这可能与人类中发生的特殊寄生虫生物学有关。通过使用基因组学，我们已经确定了完全新的寄生虫生物学，当它驻留在人类和这个项目将确定这种新的生物学是否与疾病结果的差异。这项研究汇集了计算生物学和疟疾流行病学的专家，以开发临床相关的寄生虫生物学模型，为疾病干预提供信息，以减少疟疾感染对个人和全球健康的影响。