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

基本信息

批准号：
10340527
负责人：
Rhoel David Ramos Dinglasan
金额：
$ 68.08万
依托单位：
UNIV OF NORTH CAROLINA CHAPEL HILL
依托单位国家：
美国
项目类别：
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/10340527
关键词：
Affect Africa African Anopheles Genus Antimalarials Asia Binding Proteins Biological Biological Assay Biology Blood Cameroon Cells Central Africa Clinic Community Surveys Country Culicidae Diagnostic Disease Epidemiologist Erythrocytes Ethiopia Face Foundations Genomics Genotype Human Immune Individual Infection Intervention Invaded Investigation 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 Surveys Tanzania Time Uganda Vivax Malaria Work base community clinic 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 screening single cell sequencing tool transcriptomics transmission process vector vector competence whole genome

项目摘要

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.

抽象的尽管全球在控制恶性疟原虫 (PF) 方面取得了显着进展，但卵形疟原虫 (PO) 和间日疟原虫 (PV) 可能会不断扩大，以填补留下的空白。这些疟疾种类更加困难由于早期致力于可传播的生命周期阶段（配子体）而进行控制，从而允许提前传播治疗，以及形成对血液阶段具有抵抗力的休眠肝脏阶段（休眠子）抗疟药，并可能导致日后复发感染（复发）。 PO 和 PV 更普遍非洲比以前公认的。 PO 是一种地方性流行病，是多个国家疟疾感染的一个上升原因。国家。长期以来人们认为非洲不存在PV，尽管人们普遍认为缺乏达菲蛋白，但PV仍然存在。主要红细胞 (RBC) 入侵配体，使非洲人对感染免疫。尽管越来越多的证据表明他们的负担增加，但对于控制 PO 和 PV 的关键生物参数几乎一无所知非洲的传播。主要由于缺乏现场诊断和分子工具，对 PO 和 PV 的研究非洲大部分地区几乎完全仅限于横断面患病率调查或便利性调查从诊所取样，没有尝试更深入地了解基本传播生物学以及这些物种的复发模式。该提案利用了该领域的技术进步，包括现场可部署的分子诊断、高通量基因分型和单细胞测序，提供第一个对非洲 PO 和 PV 生物学基础知识差距的深入研究。通过社区和基于临床的监测，我们将在喀麦隆 Dschang（一个合作地点）识别 PO 和 PV 感染者非洲所有 4 种主要人类疟疾均为地方病，流行病学范围最广有关中非真性红斑狼疮感染的数据。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（目标 1）、复发模式（目标 2）以及 PV 的关键信息克服限制红细胞侵袭机制的能力（目标 3）。填补这些空白将导致通过确定传染源和传染源，设计针对复发性疟疾的更适当的干预措施复发对储存库的贡献（目标 1A、2A 和 2B），以及定义目标载体干预（目标 1B）。这项工作将深入了解非洲 PV 和 PO 的机制面对针对 PF 的持续消除努力，证明具有弹性，同时生成工具（例如护理点诊断和多样性标记）来追踪这些物种。总之，这些发现将有助于设计针对复发性疟疾的新疟疾控制策略。