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

我们目前对这些因素的了解非常有限，无论是遗传的还是免疫相关的。 预防临床间日疟。破译这种保护背后的机制 将允许为消除PV而设计量身定制的干预策略。抗PV达菲的生产 结合蛋白(DBP)结合抑制抗体(BIAbs)与功能性和保护性有关 对PV疟疾的免疫力。只有少数人会产生这种抗体及其机制 使它们能够生产是未知的。不产生BIAbs的个人仍然可以预防PV 临床疟疾表明，额外的免疫和/或遗传因素可以提供保护。 利用我们在柬埔寨疫区建立的纵向队列，我们已经确定 表现出对PV的显著临床保护的个人，本提案的总体目标是 在确定使这种保护成为可能的因素方面。第一个具体目标(SA1)将是理解 驱动抗PvDBP双抗体产生的因素，从而进一步预防PV的临床保护。 自然感染的DBP特异性CD4+T细胞和B细胞的表型和功能特征 具有特征量BIAbs的参与者，我们将对获得性免疫有更好的了解 个体的反应导致自然获得的抗PvDBP BIabs的产生。另一方面， 通过对从中国大陆收集的分离株产生的PvDBP等位基因多态和异构体进行特征分析 ，我们将确定寄生虫遗传因素是否也起到了作用 收购BIAB。第二个和第三个SA将破译遗传(SA2)或免疫(SA3) 导致对不产生抗PvDBP BIabs的个体预防PV疟疾的因素。在SA2中，我们 将比较从慢性感染者分离的寄生虫的基因表达谱和基因类型 从无症状个体和有症状的寻求治疗的患者中识别寄生虫因素 区分这两种截然不同的临床结果。我们还将测定人类红细胞 感染临床结局不同个体的蛋白质多态性对宿主的识别作用 遗传因素赋予保护。任何已确定的宿主多态都将在体外进行功能测试 光伏侵袭/发育改变。在SA3中，我们将确定与保护相关的宿主免疫因素 来自临床小儿麻痹症疟疾。使用与SA2相同的患者队列，我们将在体外和体外研究免疫 PV感染患者的反应。利用抗原特异性B细胞的单细胞培养，我们的目标是识别 针对PV裂殖子或IRBC的新的体液靶点可能参与临床保护 PV疟疾通过阻断侵袭或替代抗体效应器功能。

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.