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.

项目概要 疟疾仍然是一个全球健康问题，世界上近一半人口面临传播风险。的 疟疾的临床结局很多，脑型疟是儿童死亡的主要原因。脑型疟疾是 由受感染的红细胞在脑毛细血管中积聚引起，导致血流量减少、病变、 脑肿胀，最终昏迷和死亡。受感染的红细胞与宿主受体的粘附 变异表面抗原恶性疟原虫红细胞膜促进脑内皮细胞的生长 蛋白 1 (PfEMP1)。具体来说，PfEMP1 中富含半胱氨酸的域间区域 α 1 (CIDRa1) 结构域介导 与宿主内皮蛋白 C 受体 (EPCR) 结合。疟疾流行地区的儿童克服了困难 该疾病的最初临床并发症迅速发展出针对脑型疟疾的免疫力，这是由于 获取针对 CIDRa1 的抗体。鉴于 CIDRa1 变体之间的高度序列变异和 针对其他恶性疟原虫蛋白的抗体反应迅速减弱，目前尚不清楚这种保护是如何进行的 随着时间的推移而实现并保持。我们的初步工作表明，来自疟疾的单克隆抗体- 受保护的成年人可以识别多个 CIDRa1 变体，尽管它们的序列多样性并抑制结合 这些 CIDRa1 变体到 EPCR。我们还观察到，相当大比例的 CIDRa1 靶向 B 细胞 具有非典型B细胞表型。根据我们的初步数据，我们假设广泛反应 针对 CIDRa1 的抗体针对 EPCR 结合位点周围的不同表位，并在 与持久的 B 细胞记忆相结合。在具体目标 1 中，我们将分离针对 来自疟疾记忆 B 细胞的 CIDRa1 保护成年人，阐明了广泛和重要的多样性和表位 变体特异性抗体。在具体目标 2 中，我们将定义 CIDRa1 特异性的表型和维持 使用高参数光谱流式细胞术对纵向外周血单核细胞样本进行 B 细胞分析。 这项研究的结果将增强我们对保护性免疫的性质和持久性的理解 并推进疫苗的设计，对疟疾发病机制产生广泛且长期的保护。