Comprehensive characterization of the genetic factors and the host immune response associated to protection from clinical Plasmodium vivax malaria

与预防临床间日疟原虫疟疾相关的遗传因素和宿主免疫反应的综合特征

• 批准号: 10634775
• 负责人: TINEKE CANTAERT
• 金额: $ 58.27万
• 依托单位: INSTITUT PASTEUR DU CAMBODGE
• 依托单位国家: 美国
• 财政年份: 2023
• 资助国家: 美国
• 起止时间: 2023-03-16 至 2028-02-29
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10634775
• 关键词: Alleles; Antibodies; Antigens; Area; Automobile Driving; B-Cell Antigen Receptor; B-Lymphocyte Subsets; B-Lymphocytes; B-cell receptor repertoire sequencing; Binding; Binding Proteins; Biological Assay; Blood; Blood specimen; CD4 Positive T Lymphocytes; Cambodia; Cell Culture Techniques; Cells; Characteristics; Chronic; Clinical; Data; Development; Enabling Factors; Erythrocytes; Evidence based intervention; Flow Cytometry; Future; Gene Expression; Gene Expression Profile; Genes; Genetic; Genetic Drift; Genetic Polymorphism; Genome; Genomics; Genotype; Globin; Goals; Human; Immune; Immune response; Immunity; Immunologic Factors; Immunologics; Immunophenotyping; In Vitro; Individual; Infection; Intervention; Invaded; Length; Leukocytes; Ligands; Longitudinal cohort; Malaria; Mediating; Membrane Proteins; Memory B-Lymphocyte; Messenger RNA; Minority; Minority Groups; Monoclonal Antibodies; Outcome; Parasites; Participant; Patients; Peptides; Phenotype; Plasmodium vivax; Polyadenylation Pathway; Population; Production; Protein Isoforms; Proteins; RNA; Reticulocytes; Sampling; Site; Sorting; Surface; T-Lymphocyte; Technology; Testing; Vaccines; Vivax Malaria; adaptive immune response; cohort; design; human genome sequencing; in vitro testing; individual response; inhibiting antibody; monoclonal antibody production; monocyte; morphogens; novel; novel vaccines; polyadenylated messenger RNA; protective pathway; receptor; resilience; symptom treatment; transcriptome sequencing; vaccine candidate; vaccine development; whole genome

We currently have a very limited understanding of the factors, either genetic or immune-related, conferring protection to clinical Plasmodium vivax (Pv) malaria. Deciphering the mechanisms underlying such protection would allow the design of tailored intervention strategies for the elimination of Pv. Production of anti-Pv Duffy Binding Protein (DBP) binding-inhibitory antibodies (BIabs) is associated to functional and protective immunity against Pv malaria. Only a minority of individuals develops such antibodies and the mechanisms enabling their production are unknown. Individuals not producing BIabs can still be protected against Pv clinical malaria indicating that additional immunological and/or genetic factors can confer protection. Leveraging a longitudinal cohort we have constituted in endemic area of Cambodia, we have identified individuals displaying remarkable clinical protection against Pv and the overall goal of this proposal aims at characterizing the factors enabling such protection. The first specific aim (SA1) will be to understand the factors that drive the production of anti-PvDBP BIabs and therefore further clinical protection against Pv. By phenotyping and functionally characterizing DBP-specific CD4+ T cells and B cells in naturally infected participants with characterized amounts of BIabs, we will have a better understanding of the adaptive immune response of individuals leading to the production of naturally-acquired anti-PvDBP BIabs. On the other hand, by characterizing the PvDBP allelic polymorphism and isoforms produced by isolates collected from individuals with various levels of BIabs, we will determine if parasite genetic factors are also contributing to the acquisition of BIabs. The second and third SA will be to decipher the genetic (SA2) or immune (SA3) factors leading to protection against Pv malaria for individuals not producing anti-PvDBP BIabs. In SA2, we will compare the gene expression profiles and genotypes of parasites isolated from chronically-infected asymptomatic individuals and from symptomatic treatment-seeking patients to identify parasite factors differentiating these two drastically different clinical outcomes. We will also determine the human erythrocyte proteins’ polymorphism of individuals displaying contrasted clinical outcome of infection to identify host genetic factors conferring protection. Any host polymorphism identified will be functionally tested in vitro for Pv invasion/development alterations. In SA3, we will identify host immune factors associated to protection from clinical Pv malaria. Using the same patient cohort as SA2, we will study ex vivo and in vitro the immune responses in Pv-infected patients. Using single cell cultures of antigen-specific B cells, we aim to identify novel humoral targets on the Pv merozoite or iRBC that could be involved in conferring protection from clinical Pv malaria trough blockade of invasion or alternative antibody effector functions.

目前，我们对遗传或免疫相关因素的了解非常有限。 对临床间日疟原虫 (Pv) 疟疾的保护 破译这种保护的机制。 将允许设计定制的干预策略来消除抗 Pv Duffy 的产生。 结合蛋白 (DBP) 结合抑制抗体 (BIab) 与功能性和保护性相关 只有少数人产生这种抗体及其机制。 不生产 BIab 的个人仍然可以免受 Pv 的影响。 临床疟疾表明额外的免疫和/或遗传因素可以提供保护。 利用我们在柬埔寨流行区建立的纵向队列，我们​​发现 对 Pv 表现出显着临床保护的个体，该提案的总体目标是 描述实现这种保护的因素的第一个具体目标（SA1）是了解。 驱动抗 PvDBP BIab 产生的因素，从而进一步针对 Pv 进行临床保护。 通过对自然感染的 DBP 特异性 CD4+ T 细胞和 B 细胞进行表型分析和功能表征 具有特征量 BIab 的参与者，我们将对适应性免疫有更好的了解 另一方面，个体反应导致自然获得的抗 PvDBP BIab 的产生。 通过表征从收集的分离株产生的 PvDBP 等位基因多态性和亚型 具有不同水平 BIab 的个体，我们将确定寄生虫遗传因素是否也有助于 获得 BIabs 的第二个和第三个 SA 将是破译遗传 (SA2) 或免疫 (SA3)。 在 SA2 中，导致不产生抗 PvDBP BIab 的个体免受 Pv 疟疾的因素。 将比较从慢性感染中分离出的寄生虫的基因表达谱和基因型 无症状个体和有症状寻求治疗的患者以确定寄生虫因素 我们还将确定人类红细胞区分这两种截然不同的临床结果。 个体的蛋白质多态性表现出对比的感染临床结果以识别宿主 任何鉴定出的宿主多态性都将进行体外功能测试。 在 SA3 中，我们将识别与保护相关的宿主免疫因素。 我们将使用与 SA2 相同的患者队列，研究离体和体外免疫。 我们的目标是利用抗原特异性 B 细胞的单细胞培养物来鉴定 Pv 感染患者的反应。 Pv 裂殖子或 iRBC 上的新体液靶标可能参与提供临床保护 Pv 疟疾通过阻断侵袭或替代抗体效应器功能。