Identifying functional antibody responses that protect against malaria in children

识别可预防儿童疟疾的功能性抗体反应

• 批准号: 10521648
• 负责人: Stephen Rogerson
• 金额: $ 55.91万
• 依托单位: MICHIGAN STATE UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2022
• 资助国家: 美国
• 起止时间: 2022-08-15 至 2027-07-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10521648
• 关键词: Acute; Adhesions; African; Antibodies; Antibody Avidity; Antibody Response; Antigen Targeting; Antigens; Avidity; Behavioral; Binding; Biological Assay; Biological Markers; Biophysics; Blood; Brain Edema; Cells; Cerebral Malaria; Cerebrovascular system; Cessation of life; Characteristics; Child; Clinical; Cognitive; Collection; Communities; Complement; Complex; Computational Biology; Convalescence; Data; Data Analyses; Development; Enrollment; Erythrocyte Membrane; Erythrocytes; Evolution; Fc Receptor; Genetic Transcription; Goals; Immune Targeting; Immunity; Immunology; Infection; Infection Control; Lead; Life; Longitudinal cohort; MRI Scans; Machine Learning; Magnetic Resonance Imaging; Malaria; Malaria prevention; Malawi; Measures; Mediating; Membrane Proteins; Natural Killer Cells; Outcome; Parasitemia; Parasites; Pathogenicity; Phagocytosis; Phenotype; Plasmodium falciparum; Plasmodium falciparum erythrocyte membrane protein 1; Predisposition; Pregnancy; Property; Protein Fragment; Proteins; Research; Respiratory Burst; Retina; Retinal Diseases; Serology; Site; Surface; Survivors; Syndrome; System; Technology; Therapeutic; Vaccines; Whole Blood; Woman; Work; antibody test; base; biophysical properties; clinical diagnosis; clinical phenotype; cohort; convalescent plasma; expectation; glycosylation; high risk; international center; machine learning algorithm; malaria infection; monocyte; neurovascular; neutrophil; novel strategies; placental malaria; prevent; recruit; response; skills; statistics; therapeutic development; tool; vaccine development

This project aims to identify the targets and features of antibody responses that determine the outcome of malaria infection in young African children. It uses Systems Serology, combining multi-dimensional antibody profiling with machine learning, to study responses to Plasmodium falciparum erythrocyte membrane protein 1 (PfEMP1), the dominant antigen on the surface of malaria infected erythrocytes (IEs). We also study key merozoite antigens, which are implicated in protection from asymptomatic parasitemia (AP) or uncomplicated malaria (UM). Responses include antibody subclass, isotype, and Fc receptor and complement engagement, together with antibody glycosylation and avidity. Some PfEMP1 types are implicated in cerebral malaria (CM); others may influence outcomes across a spectrum which includes AP, clearance of parasites and progression to UM. Our earlier work validates this approach. We applied Systems Serology to pregnancy malaria and were able to identify seven key responses to the PfEMP1 that mediates placental malaria (VAR2CSA), that distinguished women susceptible to placental malaria from protected women. Four of these seven were IE based assays. The proposed study is based in Blantyre, Malawi, an International Center of Excellence in Malaria Research (ICEMR) site. In ongoing studies, children with CM have retinal exams and MRI scans to assess neurovascular involvement and brain swelling, respectively. Cohorts of controls with UM and community controls with AP are enrolled and sustained. In Aim 1, we use Luminex technology on acute and convalescent plasma and parasite isolates to characterize antibody response to a broad range of PfEMP1 protein fragments implicated in severe malaria. From these analyses we will identify antibody responses to PfEMP1 domains that are lacking in children with CM, that differ between children with or without retinopathy and brain swelling, and that develop in convalescence from CM. In Aim 2, priority PfEMP1s identified in Aim 1 are studied in depth using cell-based assays of phagocytosis, respiratory burst and activation with both PfEMP1 fragments and parasite lines expressing similar PfEMP1 types. We have established assays using monocytes, neutrophils, NK cells and whole blood for this purpose. Aim 3 uses community cohorts recruited by the Malawi ICEMR, including children with AP, to study how antibodies to PfEMP1 and to merozoite antigens influence the evolution of AP, to identify antibody responses that prevent progression to UM or lead to clearance of infection. These comprehensive, integrated studies will compare and contrast antibody responses that protect against CM, against UM, and that clear parasitemia. Identifying the targets and properties of antibodies to PfEMP1 that are associated with protection from life threatening malaria in African children will be key to developing tailored vaccines or therapeutics to prevent or treat severe malaria. Discovering key protective antibody responses across the malaria infection spectrum will reveal the importance of antibody to PfEMP1 and merozoites for malaria control and elimination.

该项目旨在确定决定疟疾结果的抗体反应的目标和特征 非洲幼儿感染。它使用系统血清学，结合多维抗体分析 通过机器学习，研究对恶性疟原虫红细胞膜蛋白 1 (PfEMP1) 的反应， 疟疾感染的红细胞（IE）表面的显性抗原。我们还研究关键的裂殖子抗原， 这与预防无症状寄生虫血症（AP）或单纯性疟疾（UM）有关。 反应包括抗体亚类、同种型、Fc 受体和补体结合，以及 抗体糖基化和亲合力。一些 PfEMP1 类型与脑型疟疾 (CM) 有关；其他人可能 影响一系列结果，包括 AP、寄生虫清除和 UM 进展。我们的 早期的工作验证了这种方法。我们将系统血清学应用于妊娠期疟疾，并且能够 确定了对介导胎盘疟疾 (VAR2CSA) 的 PfEMP1 的七种关键反应，这区分了 受保护妇女易患胎盘疟疾的妇女。这七个中的四个是基于 IE 的检测。 拟议的研究位于马拉维布兰太尔国际疟疾研究卓越中心 （ICEMR）网站。在正在进行的研究中，患有 CM 的儿童接受视网膜检查和 MRI 扫描来评估神经血管 分别是受累和脑肿胀。具有 UM 的控制组和具有 AP 的社区控制组是 注册并持续。在目标 1 中，我们对急性和恢复期血浆和寄生虫使用 Luminex 技术 分离株来表征对与严重疾病有关的广泛 PfEMP1 蛋白片段的抗体反应 疟疾。从这些分析中，我们将确定儿童中缺乏的对 PfEMP1 结构域的抗体反应 CM，在患有或不患有视网膜病变和脑肿胀的儿童之间存在差异，并且在 CM 康复期。 在目标 2 中，使用基于细胞的吞噬作用测定深入研究了目标 1 中确定的优先 PfEMP1， PfEMP1 片段和表达相似 PfEMP1 类型的寄生虫系的呼吸爆发和激活。 为此，我们已经使用单核细胞、中性粒细胞、NK 细胞和全血建立了检测方法。 目标 3 利用马拉维 ICEMR 招募的社区队列（包括患有 AP 的儿童）来研究如何 PfEMP1 和裂殖子抗原的抗体影响 AP 的进化，以确定抗体反应 防止进展为 UM 或导致感染清除。这些全面、综合的研究将 比较和对比针对 CM、UM 和清除寄生虫血症的抗体反应。 识别与生命保护相关的 PfEMP1 抗体的靶标和特性 威胁非洲儿童的疟疾将是开发定制疫苗或疗法来预防或治疗的关键 治疗严重的疟疾。发现整个疟疾感染谱中的关键保护性抗体反应将 揭示了 PfEMP1 和裂殖子抗体对于控制和消除疟疾的重要性。