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靶点和特征