Molecular and cellular properties of broad and protective immune responses to the Plasmodium falciparum variant surface antigen responsible for severe malaria

针对导致严重疟疾的恶性疟原虫变异表面抗原的广泛和保护性免疫反应的分子和细胞特性

• 批准号: 10609430
• 负责人: Raphael Anthony Reyes
• 金额: $ 0.99万
• 依托单位: UNIVERSITY OF TEXAS HLTH SCIENCE CENTER
• 依托单位国家: 美国
• 财政年份: 2022
• 资助国家: 美国
• 起止时间: 2022-05-01 至 2023-06-02
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10609430
• 关键词: Adhesions; Adult; Affinity; Antibodies; Antibody Response; Antigens; B-Lymphocyte Subsets; B-Lymphocytes; Binding; Binding Sites; Biological Assay; Blood flow; Brain; Brain Edema; Cause of Death; Cells; Cellular biology; Cerebral Malaria; Cessation of life; Characteristics; Child; Clinical; Coma; Complement 3d Receptors; Cryopreservation; Cysteine; Data; Development; Disease; Endothelium; Epitope Mapping; Epitopes; Erythrocytes; Exposure to; Family; Flow Cytometry; Heterogeneity; Immune response; Immunity; Immunologics; Infection; Lesion; Maintenance; Malaria; Malaria Vaccines; Maps; Mediating; Memory; Memory B-Lymphocyte; Molecular; Monoclonal Antibodies; Nature; Outcome; Parasites; Pathogenesis; Peripheral Blood Mononuclear Cell; Phenotype; Phylogenetic Analysis; Plasmodium; Plasmodium falciparum; Plasmodium falciparum erythrocyte membrane protein 1; Population; Populations at Risk; Positioning Attribute; Property; Protein Family; Proteins; Risk; Sampling; Shapes; Surface; Surface Antigens; Tertiary Protein Structure; Testing; Time; Uganda; Vaccination; Vaccines; Variant; Vascular Endothelium; Virulent; Work; acquired immunity; activated protein C receptor; cerebral capillary; cohort; design; experience; global health; insight; mutant; novel vaccines; prevent; receptor; receptor binding; response; transmission process

PROJECT SUMMARY Malaria remains a global health problem, with nearly half the world’s population at risk of transmission. Of the many clinical outcomes of malaria, cerebral malaria is the major cause of death in children. Cerebral malaria is caused by the accumulation of infected erythrocytes in brain capillaries, resulting in reduced blood flow, lesions, brain swelling, and ultimately coma and death. The adhesion of infected erythrocytes to host receptors found on brain endothelium is facilitated by the variant surface antigen Plasmodium falciparum erythrocyte membrane protein 1 (PfEMP1). Specifically, cysteine-rich interdomain region alpha 1 (CIDRa1) domains in PfEMP1 mediate binding to host endothelial protein C receptor (EPCR). Children in malaria-endemic regions who overcome the initial clinical complications of the disease rapidly develop immunity against cerebral malaria, resulting from the acquisition of antibodies targeting CIDRa1. Given the high sequence variation among CIDRa1 variants and the quick waning of antibody responses against other P. falciparum proteins, it is unclear how this protection is achieved and maintained over time. Our preliminary work has revealed that monoclonal antibodies from malaria- protected adults can recognize multiple CIDRa1 variants despite their sequence diversity and inhibit the binding of these CIDRa1 variants to EPCR. We also observed that a substantial percentage of CIDRa1-targeting B cells possessed an atypical B cell phenotype. Based on our preliminary data, we hypothesize that broadly reactive antibodies against CIDRa1 target diverse epitopes around the EPCR-binding site and are generated in conjunction with long-lasting B cell memory. In Specific Aim 1, we will isolate monoclonal antibodies against CIDRa1 from memory B cells of malaria protected adults to elucidate the diversity and epitopes of broad and variant specific antibodies. In Specific Aim 2, we will define the phenotype and maintenance of CIDRa1-specific B cells using high parameter spectral flow cytometry on longitudinal peripheral blood mononuclear cell samples. The results from this study will enhance our understanding of the nature and durability of protective immunity and advance the design of a vaccine that elicits broad and long-lived protection against malaria pathogenesis.

项目摘要 疟疾仍然是一个全球健康问题，几乎一半的世界人口有传播风险。的 疟疾的许多临床结果，脑疟疾是儿童死亡的主要原因。 由脑毛细血管中感染红细胞的积累引起的，导致血流，病变，病变降低 脑肿胀，最终昏迷与死亡。受感染的红细胞的粘合剂对宿主受体发现 脑内皮由变体的表面抗原疟原虫恶性红细胞膜膜制备 蛋白1（PFEMP1）。特定于PFEMP1中的富含半胱氨酸的域间区域Alpha 1（CIDRA1）域介导 与宿主内皮蛋白C受体（EPCR）结合。克服疟疾的儿童 - 内态地区 该疾病的初始临床并发症迅速产生免疫力针对脑疟疾的免疫力，这是由于 靶向CIDRA1的抗体的获取。鉴于CIDRA1变体之间的较高序列变化和 抗体反应的快速减弱针对其他恶性疟原虫蛋白，目前尚不清楚这种保护是如何的 随着时间的流逝而实现和维护。我们的初步工作表明，疟疾的单克隆抗体 - 受保护的成年人可以识别多个cidra1变体可以执行其序列多样性并抑制结合 这些cidra1变体为epcr。我们还观察到大量靶向CIDRA1的B细胞 具有非典型B细胞表型。基于我们的初步数据，我们假设这种广泛反应性 针对CIDRA1的抗体靶向EPCR结合位点周围的不同表位，并在 与持久的B单元存储器连接。在特定的目标1中，我们将分离单克隆抗体 来自疟疾的记忆B细胞的CIDRA1保护成年人，以阐明宽阔的多样性和表位 变体特异性抗体。在特定目标2中，我们将定义CIDRA1特异性的表型和维护 B细胞使用纵向外周血单核细胞样品上的高参数光谱流式细胞仪。 这项研究的结果将增强我们对保护性免疫的性质和耐用性的理解 并推进疫苗的设计，该疫苗对疟疾发病机理产生广泛和长期保护的保护。