Analysis of novel in vivo derived Plasmodium falciparum transcriptional profiles

新型体内恶性疟原虫转录谱分析

基本信息

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
项目类别：
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

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

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项目摘要

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）：恶性疟原虫疟原虫的感染导致儿童的临床状况截然不同 - 从轻度流感症状到昏迷和昏迷和死亡。尽管有巨大的医学意义，但这种多样性的遗传和分子基础在很大程度上仍然未知。我们假设居住在人类宿主中的寄生虫需要适应这种专业环境，该环境在温度，底物和免疫反应上有所不同。为了表征寄生虫生物学，我们利用了感染患者新鲜血液样本的寄生虫的整个基因组分析。通过这种方法，我们确定了寄生虫居住在人类宿主中时的三种生物状态。这些体内状态之一与实验室成长的转录概况高度相关，现在我们已经确定了两个新的状态。这些状态的生物学基础可以与酵母中酿酒酵母中表达数据广泛的表达数据进行比较来解释。这三个州的体内与基于糖酵解代谢的“体外状态”的活性生长非常相似（i）；（ii）饥饿反应伴随着氧化磷酸化；（iii）环境压力反应。该结果揭示了以前未知的疟原虫体内生物学生物学多样性，尤其是在无性阶段寄生虫中功能性线粒体的证据，并指向体内和体外研究，以确定这种变异如何影响疾病的表现和治疗。这项工作强调了与人类样品一起探索临床相关的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）确定与这些新型生物状态相关的宿主因素2）确定在严重疾病中特异性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。我们正在为该寄生虫中的宿主病原体相互作用开发一个完全新颖的模型。临床研究为体外模型提供了信息，相反，该模型的结果可以前瞻性地在临床研究中进行测试。此外，我们还发展了临床疟疾，计算生物学和分子生物学领域的领导者团队，以结合他们的技能，以进一步了解我们对疾病的理解。长期目标是确定可以针对降低恶性疟原虫的个体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，这些感染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有些患者完全可以很好地理解，这可能与人类发生的专门寄生虫生物学有关。通过使用基因组学，我们已经确定了全新的寄生虫生物学居住在人类中时，该项目将确定这种新型生物学是否与疾病结局的差异有关。这项研究汇集了计算生物学和疟疾流行病学专家，以开发临床相关的寄生虫生物学模型，以告知疾病干预措施，以减少疟疾感染对个体和全球健康的影响。