Defining clinical and sterile immunity to Plasmodium falciparum infection using systems biology approaches

项目摘要/摘要 每年约有1.98亿人患疟疾，其中43.8万人死于恶性疟原虫， 强调需要一种高效的疟疾疫苗。首个获得许可的疟疾疫苗，RTS，S，可能 在发病率和死亡率方面提供了亟需的降低，但在减少临床疟疾方面效果不佳 在非洲婴儿的目标人群中，这一比例有很大的提高空间。更好地理解 自然暴露人群对恶性疟原虫的免疫可促进改进疟疾疫苗的努力 设计。到目前为止，还没有可靠的相关性可以预防有症状的恶性疟原虫感染。 (临床免疫)或寄生虫血症(无菌免疫)。系统生物学利用大型生物的计算模型 扩展数据集以阐明复杂的生物网络，并有可能揭示新的预测因素和 应用于精心设计的临床队列研究时的疟疾保护机制。 在这个项目中，候选人建议评估恶性疟原虫自然保护的免疫预测因子。 使用系统生物学方法进行感染。通过分析临床数据和从一家医院收集的血液样本 对恶性疟原虫免疫程度不同的马里儿童的特征良好的预期队列 感染，候选人将解决两个主要研究目标：1)确定免疫参数预测 防止症状感染(临床免疫)和保护免受恶性疟原虫感染(无菌 免疫)和2)将这些免疫参数和结果与从这些免疫参数和结果获得的血浆的能力联系起来 体外能抑制寄生虫侵入肝脏和红细胞。这项工作的实际意义 包括识别新免疫预测因子和预防恶性疟原虫感染的机制以及 疫苗目标人群中的疾病可以为候选疟疾提供合理的基准 疫苗。 候选人坚定地致力于转译疟疾研究和系统生物学的职业生涯，并 他的职业生涯和研究目标得到了他的导师和印第安纳大学分部的大力支持 医学院。他目前担任医学助理教授，80%受到保护 用于研究的时间，独立实验室和办公空间，以及设备资金。目前的提案 包括全面的指导和教学计划，以提高候选人的技能和知识 发展系统生物学专业知识所需的生物统计学和计算生物学。在.之下 他的主要导师Chandy John博士和他的合作导师屠婉珠博士、郎力博士和Dr。 彼得·克伦普顿，他将提高他的生物信息学技能，并学习预测建模方法， 将直接适用于这项提案。完成这一全面培训计划将为应聘者提供 具备成为一名成功的独立调查员所需的技能和经验 计算系统生物学，重点研究宿主对疟原虫感染的免疫。

Project Summary/Abstract Malaria afflicts ~198 million people yearly, with 438,000 malaria deaths due to Plasmodium falciparum, underscoring the need for a highly effective malaria vaccine. The first licensed malaria vaccine, RTS,S, may provide much-needed reductions in morbidity and mortality, but its modest efficacy in reducing clinical malaria in the target population of African infants leaves ample margin for improvement. A better understanding of immunity to P. falciparum in naturally exposed populations can inform efforts to improve malaria vaccine design. To date, there are no reliable correlates of protection from either symptomatic P. falciparum infection (clinical immunity) or parasitemia (sterile immunity). Systems biology utilizes computational modeling of large- scale data sets to elucidate complex biological networks and has the potential to reveal novel predictors and mechanisms of malaria protection when applied to well-designed clinical cohort studies. In this project, the candidate proposes to assess immune predictors of natural protection from P. falciparum infection using systems biology approaches. By analyzing clinical data and blood specimens collected from a well-characterized, prospective cohort of Malian children who differ in their degree of immunity to P. falciparum infection, the candidate will address two main research aims: 1) determine immune parameters predictive of protection from symptomatic infection (clinical immunity) and protection from P. falciparum infection (sterile immunity) and 2) relate these immune parameters and outcomes to the ability of plasma obtained from these children to inhibit parasite invasion into liver and red blood cells in vitro. The practical implications of this work include identifying novel immune predictors and mechanisms of protection from P. falciparum infection and disease within the vaccine target population that could provide rational benchmarks for candidate malaria vaccines. The candidate is firmly committed to a career in translational malaria research and systems biology and is strongly supported in his career and research goals by his mentors and his division at the Indiana University School of Medicine. He currently holds a position as an Assistant Professor of Medicine with 80% protected time for research, independent laboratory and office space, and funding for equipment. The current proposal includes a comprehensive mentorship and didactic plan to advance the candidate's skills and knowledge in biostatistics and computational biology required for developing expertise in systems biology. Under the guidance of his primary mentor, Dr. Chandy John, and his co-mentors, Dr. Wanzhu Tu, Dr. Lang Li, and Dr. Peter Crompton, he will advance his bioinformatics skills and learn predictive modeling methodologies that will be directly applied to this proposal. Completion of this comprehensive training plan will provide the candidate with the skills and experience necessary to become a successful independent investigator specializing in computational systems biology with a focus on host immunity to Plasmodium infection.