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

使用系统生物学方法定义针对恶性疟原虫感染的临床和无菌免疫

• 批准号: 10097958
• 负责人: Tuan Manh Tran
• 金额: $ 18.52万
• 依托单位: INDIANA UNIV-PURDUE UNIV AT INDIANAPOLIS
• 依托单位国家: 美国
• 财政年份: 2017
• 资助国家: 美国
• 起止时间: 2017-02-10 至 2023-01-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10097958
• 关键词: Accounting; Address; Africa; African; Antibodies; Antigens; Area; B-Lymphocytes; Benchmarking; Bioinformatics; Biological; Biometry; Blood; Blood specimen; Cessation of life; Child; Childhood; Clinical; Clinical Data; Cohort Studies; Complex; Computational Biology; Computer Models; Confounding Factors (Epidemiology); Data; Development; Disease; Equipment; Erythrocytes; Exposure to; Flow Cytometry; Funding; Future; Generations; Genetic; Goals; Hepatocyte; Human; Immune; Immunity; Immunoglobulin G; Immunologic Factors; In Vitro; Indiana; Infant; Infection; Interferon Type II; Interferons; Knowledge; Laboratories; Learning; Liver; Malaria; Malaria Vaccines; Medicine; Mentors; Mentorship; Methodology; Molecular; Morbidity - disease rate; Natural Immunity; Outcome; Parasitemia; Parasites; Plasma; Plasmodium falciparum; Population; Positioning Attribute; Prospective cohort; Research; Research Personnel; Role; Sampling; Statistical Models; Sterility; Symptoms; Systems Biology; Target Populations; Time; Training; Universities; Vaccine Design; Vaccines; Work; base; career; clinical predictors; cohort; cytokine; design; experience; experimental study; field study; improved; in vitro activity; insight; large scale data; machine learning algorithm; malaria transmission; medical schools; mortality; next generation; novel; parasite invasion; predictive modeling; predictive signature; professor; prospective; response; skills; surveillance data; transcriptomics; vaccination outcome; vaccine candidate

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.

项目总结/摘要 每年约有1.98亿人感染疟疾，其中43.8万人死于恶性疟原虫， 强调需要高效的疟疾疫苗。第一种获得许可的疟疾疫苗RTS，S， 提供急需的发病率和死亡率的降低，但其在减少临床疟疾方面的效力有限， 在非洲婴儿这一目标人群中，仍有很大的改进余地。更好地了解 自然暴露人群对恶性疟原虫的免疫力可以为改进疟疾疫苗的努力提供信息 设计到目前为止，没有可靠的相关保护症状恶性疟原虫感染 （临床免疫）或寄生虫血症（无菌免疫）。系统生物学利用计算建模的大型- 规模数据集，以阐明复杂的生物网络，并有可能揭示新的预测因子， 当应用于精心设计的临床队列研究时，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血液标本， 对恶性疟原虫免疫程度不同的马里儿童的一个特征明确的前瞻性队列 感染，候选人将解决两个主要的研究目标：1）确定免疫参数预测 预防症状性感染（临床免疫）和预防恶性疟原虫感染（无菌 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相关联。 在体外抑制寄生虫侵入儿童肝脏和红细胞。这项工作的实际意义 包括鉴定新的免疫预测因子和保护免受恶性疟原虫感染的机制， 可为候选疟疾提供合理基准的疫苗目标人群中的疾病 疫苗。 候选人坚定地致力于转化疟疾研究和系统生物学的职业生涯， 他的导师和他在印第安纳州大学的部门对他的职业和研究目标给予了大力支持 医学院的。他目前担任医学助理教授， 研究时间、独立的实验室和办公空间以及设备资金。现时的建议 包括全面的指导和教学计划，以提高候选人的技能和知识， 生物统计学和计算生物学所需的发展系统生物学的专业知识。下 在他的主要导师Chandy John博士和他的共同导师Wanzhu Tu博士，Lang Li博士和Dr. 彼得·克朗普顿，他将提高他的生物信息学技能，并学习预测建模方法， 直接适用于本提案。完成这一全面的培训计划将为候选人提供 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，重点是疟原虫感染的宿主免疫。

项目成果

Synergistic malaria vaccine combinations identified by systematic antigen screening.

• DOI: 10.1073/pnas.1702944114
• 发表时间: 2017-11-07
• 期刊: Proceedings of the National Academy of Sciences of the United States of America
• 影响因子: 11.1
• 作者: Bustamante LY;Powell GT;Lin YC;Macklin MD;Cross N;Kemp A;Cawkill P;Sanderson T;Crosnier C;Muller-Sienerth N;Doumbo OK;Traore B;Crompton PD;Cicuta P;Tran TM;Wright GJ;Rayner JC
• 通讯作者: Rayner JC

Reply to Liu et al.

回复刘等人。

• DOI: 10.1093/infdis/jiz121
• 发表时间: 2019
• 期刊: The Journal of infectious diseases
• 作者: Nallandhighal,Srinivas;Tran,TuanM
• 通讯作者: Tran,TuanM

The prevalence and density of asymptomatic Plasmodium falciparum infections among children and adults in three communities of western Kenya.

• DOI: 10.1186/s12936-021-03905-w
• 发表时间: 2021-09-17
• 期刊: Malaria journal
• 影响因子: 3
• 作者: Salgado C;Ayodo G;Macklin MD;Gould MP;Nallandhighal S;Odhiambo EO;Obala A;O'Meara WP;John CC;Tran TM
• 通讯作者: Tran TM

Experience counts in the malaria response.

经验在疟疾应对中很重要。

• DOI: 10.1038/s41590-021-00917-1
• 发表时间: 2021
• 期刊: Nature immunology
• 影响因子: 30.5
• 作者: Holla,Prasida;Tran,TuanM
• 通讯作者: Tran,TuanM

Accumulation of Neutrophil Phagocytic Antibody Features Tracks With Naturally Acquired Immunity Against Malaria in Children.

中性粒细胞吞噬抗体的积累具有儿童对疟疾的自然获得性免疫力。

• DOI: 10.1093/infdis/jiad115
• 发表时间: 2023
• 期刊: The Journal of infectious diseases
• 作者: Nziza,Nadege;Tran,TuanM;DeRiso,ElizabethA;Dolatshahi,Sepideh;Herman,JonathanD;deLacerda,Luna;Junqueira,Caroline;Lieberman,Judy;Ongoiba,Aissata;Doumbo,Safiatou;Kayentao,Kassoum;Traore,Boubacar;Crompton,PeterD;Alter,Galit
• 通讯作者: Alter,Galit