Relapsing malaria in Africa: mechanisms for persistence amid falciparum decline

摘要 尽管全球在控制恶性疟原虫（PF）方面取得了重大进展，但卵形疟原虫（PO）和 间日疟原虫（PV）可能正在扩大，以填补留下的利基。这些疟疾种类 由于早期进入可传播的生命周期阶段（配子体）， 治疗，并通过形成休眠的肝脏阶段（催眠虫），这是抵抗血液阶段 抗疟疾药物，并可能导致在以后的日期复发感染（复发）。PO和PV在以下人群中更为普遍： 非洲比以前认识到。PO是一种地方性疾病，是多个国家疟疾感染的一个上升原因。 国家PV，长期以来被认为是非洲所没有的，尽管缺乏达菲蛋白， 主要的红细胞（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 由于它们的负担增加，几乎对控制PO和PV的关键生物学参数一无所知 在非洲传播。大多数情况下，由于缺乏现场诊断和分子工具， 大多数非洲国家几乎完全局限于横断面流行率调查或方便 从诊所取样，没有试图深入了解基本的传播生物学 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 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生物学的这些基本知识差距进行了强有力的研究。通过社区和 基于临床的监测，我们将确定PO和PV感染的个人在德昌喀麦隆，一个网站共同， 非洲所有4种主要人类疟疾的地方病， 关于非洲中部PV感染的数据。通过结合人类、载体和基因组研究， 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RBC侵入的机制的能力（目的3）。填补这些空白将导致 通过界定传染源和疟疾复发的原因， 复发对储库的贡献（目标1A，2A和2B），以及定义靶向载体 （目标1B）。这项工作将提供深入了解的机制，通过这种机制，PV和PO在非洲可能 面对针对PF的持续消除努力，证明具有弹性，同时产生工具 (e.g.即时诊断和多样性标记）来追踪这些物种。这些发现将有助于 制定针对复发疟疾的新的疟疾控制战略。

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.