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

基本信息

批准号：
10684076
负责人：
Stephen Rogerson
金额：
$ 52.94万
依托单位：
MICHIGAN STATE UNIVERSITY
依托单位国家：
美国
项目类别：
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/10684076
关键词：
Acceleration Acute Adhesions African Antibodies Antibody Avidity Antibody Response Antibody-mediated protection 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 Dimensions 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 Visualization Whole Blood Woman Work antibody test biomarker identification 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

项目摘要

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靶标和特征年轻儿童感染。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，疟疾表面上的主要抗原感染了红细胞（IES）。我们还研究关键的梅罗济岩抗原，与保护无症状寄生虫（AP）或简单疟疾（UM）有关。响应包括抗体亚类，同种型和FC受体以及补体参与，以及抗体糖基化和亲和力。某些PFEMP1类型与脑疟疾有关（CM）。其他人可能在包括AP，清除寄生虫和向UM的过程中的范围内的影响结果。我们的较早的工作验证了这种方法。我们将血清学应用于妊娠疟疾，能够确定对介导胎盘疟疾（VAR2CSA）的PFEMP1的七个关键反应，妇女容易受到保护妇女的胎盘疟疾。这七个是IE基于IE的四个测定法。拟议的研究设在马拉维的布兰特尔，这是国际疟疾研究卓越中心（ICEMR）站点。在正在进行的研究中，CM儿童进行视网膜检查和MRI扫描以评估神经血管分别参与和大脑肿胀。具有UM和AP的社区控制的控制组是注册和持续。在AIM 1中，我们在急性和康复等离子体和寄生虫上使用Luminex技术分离株表征对涉及严重的PFEMP1蛋白片段的抗体反应疟疾。从这些分析中，我们将确定儿童缺乏PFEMP1域的抗体反应使用CM，患有或没有视网膜病变和脑肿胀的儿童之间的不同，这种情况就会发展 CM的恢复。在AIM 2中，使用基于细胞的吞噬作用，深入研究了AIM 1中确定的PFEMP1的优先级PFEMP1。 PFEMP1片段和表达相似PFEMP1类型的呼吸爆发和激活。为此，我们已经建立了使用单核细胞，中性粒细胞，NK细胞和全血的测定法。 AIM 3使用马拉维ICEMR招募的社区人群，包括AP儿童，以研究如何研究对PFEMP1的抗体和Merozoite抗原影响AP的演变，以鉴定抗体反应这可以防止进展或导致感染的清除。这些全面的综合研究将比较和对比抗体反应，以防止CM，免受UM和清晰的寄生虫病。识别与生命免受保护有关的抗体抗体的靶标和特性威胁非洲儿童疟疾将是开发量身定制的疫苗或治疗剂以预防或治疗严重的疟疾。在疟疾感染谱中发现关键的保护性抗体反应将揭示了抗体对PFEMP1和蛋白酶对疟疾控制和消除的重要性。