Relapsing malaria in Africa: mechanisms for persistence amid falciparum decline

非洲疟疾复发：恶性疟下降期间的持续机制

• 批准号: 10670794
• 负责人: Rhoel David Ramos Dinglasan
• 金额: $ 64.96万
• 依托单位: UNIV OF NORTH CAROLINA CHAPEL HILL
• 依托单位国家: 美国
• 财政年份: 2022
• 资助国家: 美国
• 起止时间: 2022-07-25 至 2027-06-30
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10670794
• 关键词: Affect; Africa; African; Anopheles Genus; Antimalarials; Asia; Binding Proteins; Biological; Biological Assay; Biology; Blood; Cameroon; Cells; Central Africa; Clinic; Communities; Community Surveys; Country; Culicidae; Diagnostic; Disease; Epidemiologist; Erythrocytes; Ethiopia; Face; Genomics; Genotype; Human; Immune; Individual; Infection; Intervention; Invaded; Investigation; Investments; Kenya; Knowledge; Larva; Left; Life Cycle Stages; Ligands; Liver; Longitudinal cohort; Madagascar; Malaria; Molecular; Monitor; Parasitemia; Parasites; Pattern; Periodicity; Plasmodium falciparum; Plasmodium ovale; Plasmodium vivax; Prevalence; Production; Proteins; Proteomics; Relapse; Research; Research Personnel; Resistance; Sampling; Shapes; Site; Skin; Sorting; Surveys; Tanzania; Time; Uganda; Vivax Malaria; Work; deep sequencing; density; design; epidemiologic data; evidence base; feeding; genome sequencing; genomic locus; genomic tools; insight; malaria infection; molecular diagnostics; neglect; point of care; point-of-care diagnostics; recurrent infection; relapse prediction; resilience; screening; single cell sequencing; tool; transcriptomics; transmission process; vector; vector competence; whole genome

ABSTRACT Despite significant gains in the control of Plasmodium falciparum (PF) globally, Plasmodium ovale (PO) and Plasmodium vivax (PV) may be expanding to fill the niche left behind. These malaria species are more difficult to control due to early commitment to transmissible life cycle stages (gametocytes), allowing transmission prior to treatment, and by the formation of dormant liver stages (hypnozoites) which are resistant to blood stage antimalarial drugs and can cause recurrent infection at a later date (relapse). PO and PV are more prevalent in Africa than previously recognized. PO, known to be endemic, is a rising cause of malaria infections in multiple countries. PV, long thought absent from Africa, has persisted despite the dogma that the lack of Duffy protein, the main red cell (RBC) invasion ligand, renders Africans immune to infection. Despite the growing evidence of their increased burden, almost nothing is known about key biologic parameters that govern PO and PV transmission in Africa. Largely due to the lack of field diagnostics and molecular tools, studies of PO and PV in most of Africa have almost exclusively been limited to cross-sectional prevalence surveys or convenience sampling from clinics, without any attempt to gain a deeper understanding of the basic transmission biology and relapse patterns of these species. This proposal leverages technical advances in the field, including field deployable molecular diagnostics, high throughput genotyping and single cell sequencing, to provide the first robust studies of these fundamental knowledge gaps in PO and PV biology in Africa. Through community and clinic-based surveillance, we will identify PO and PV infected individuals in Dschang Cameroon, a site co- endemic for all 4 major species of human malaria in Africa and which has the most extensive epidemiologic data concerning PV infection in Central Africa. By combining human, vector and genomic studies, the proposal will provide key information about transmission biology (Aim 1), relapse patterns (Aim 2) and, for PV, the ability to overcome the mechanisms that restrict RBC invasion (Aim 3). Filling in these gaps will lead to the design of more appropriate interventions for relapsing malaria by defining the infectious reservoir and the contribution of relapse to the reservoir (Aim 1A, 2A and 2B), as well as defining vectors for targeted intervention (Aim 1B). This work will provide insight into the mechanisms by which PV and PO in Africa may prove resilient in the face of continued elimination efforts targeting PF and at the same time generate tools (e.g. point-of-care diagnostics and diversity markers) to track these species. Together, these findings will help shape the design of new malaria control strategies for relapsing malarias.

抽象的 尽管全球疟原虫（PF）的控制大幅增长，但椭圆形疟原虫（PO）和 Vivax疟原虫（PV）可能正在扩展，以填充留下的利基市场。这些疟疾物种更困难 由于早期承诺可传播生命周期阶段（配子细胞）而控制的控制，允许之前传播 进行治疗，并通过对血液阶段有抵抗力的休眠肝阶段（催眠率）形成 抗疟药，并可能在以后引起复发感染（复发）。 PO和PV在 非洲比以前认可的非洲。 PO，已知是流行的，是多种疟疾感染的兴起的原因 国家。尽管缺乏达菲蛋白的教条，但PV长期以来一直没有非洲的想法，但仍在 主红细胞（RBC）入侵配体使非洲人免疫感染。尽管有越来越多的证据表明 他们的负担增加了，几乎没有关于控制PO和PV的关键生物学参数的了解 非洲传播。很大程度上是由于缺乏现场诊断和分子工具，对PO和PV的研究 大多数非洲几乎仅限于横断面的患病率调查或便利性 从诊所进行取样，无需任何试图深入了解基本传播生物学 和这些物种的复发模式。该建议利用该领域的技术进步，包括领域 可部署的分子诊断，高通量基因分型和单细胞测序，以提供第一个 对非洲PO和PV生物学的这些基本知识差距的强大研究。通过社区和 基于诊所的监视，我们将在Dschang Cameroon中确定PO和PV感染的个体，这是一个站点共同的 非洲所有4种主要人类疟疾的主要种类，并且具有最广泛的流行病学 有关中非PV感染的数据。通过结合人类，载体和基因组研究，该提案 将提供有关传播生物学（AIM 1），复发模式（AIM 2）以及PV的关键信息 能够克服限制RBC入侵的机制（AIM 3）。填补这些空白将导致 设计更适当的干预措施，以通过定义感染性储层和 对水库复发的贡献（AIM 1A，2A和2B），并定义针对目标的向量 干预（目标1B）。这项工作将洞悉非洲PV和PO的机制 面对针对PF的持续消除工作，证明有韧性，同时生成工具 （例如，护理点诊断和多样性标记）跟踪这些物种。这些发现在一起将有所帮助 塑造用于复发疟疾的新疟疾控制策略的设计。