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的因素的了解非常有限 保护临床疟原虫疟疾。破解这种保护的基础机制 将允许设计量身定制的干预策略来消除PV。抗PV Duffy的生产 结合蛋白（DBP）结合抑制性抗体（BIAB）与功能和保护有关 免疫对光伏疟疾的免疫力。只有少数人会发展出这种抗体和机制 实现他们的生产是未知的。仍然可以保护未产生BIAB的个体免受PV的保护 临床疟疾表明其他免疫学和/或遗传因素可以提供保护。 利用我们在柬埔寨的内在区域构成的纵向队列，我们​​已经确定了 表现出对PV的显着临床保护的个人以及该提案的总体目标 表征实现这种保护的因素。第一个特定目标（SA1）将是了解 推动抗PVDBP BIAB的产生的因素，从而进一步抗PV的临床保护。 通过表型和功能表征DBP特异性CD4+ T细胞和B细胞自然感染 具有特征数量的BIAB的参与者，我们将对适应性免疫有更好的了解 导致自然获得的抗PVDBP BIAB的个体的反应。另一方面， 通过表征从从中收集的分离株产生的PVDBP等位基因多态性和同工型 具有不同水平的BIAB的个体，我们将确定寄生虫遗传因素是否也有助于 收购BIAB。第二和第三SA将是破译遗传（SA2）或免疫（SA3） 导致防止PV疟疾的因素，对于未产生抗PVDBP BIAB的个体。在SA2中，我们 将比较从慢性感染的寄生虫的基因表达谱和基因型 无症状的个体和从症状治疗的患者来识别寄生虫因素 区分这两个截然不同的临床结果。我们还将确定人类红细胞 蛋白质的蛋白质对表现出对比临床结果的个体的多态性，以鉴定宿主 遗传因素会议保护。确定的任何宿主多态性将在体外进行功能测试 PV入侵/发展改变。在SA3中，我们将确定与保护相关的宿主免疫因素 来自临床光伏疟疾。使用与SA2相同的患者队列，我们​​将在体内研究并体外免疫 PV感染患者的反应。使用抗原特异性B细胞的单细胞培养物，我们旨在识别 可能与临床保护有关的PV Merozoite或IRBC的新型体液靶 PV疟疾凹槽阻断入侵或替代抗体效应子功能。