Relapsing malaria in Africa: mechanisms for persistence amid falciparum decline

摘要 尽管在全球控制恶性疟原虫方面取得了重大进展，但卵形疟原虫(PO)和 间日疟原虫(PV)可能正在扩张，以填补留下的利基。这些疟疾物种更难 由于早期致力于可传递的生命周期阶段(配子体)而进行控制，允许优先传递 通过形成对血液阶段具有抵抗力的休眠的肝脏阶段(催眠体)来治疗 抗疟疾药物，并可在以后引起复发感染(复发)。PO和PV在中国更普遍 非洲比以前认识到的更多。已知的地方病是疟疾感染的一个不断上升的原因。 国家。长期以来，人们认为非洲没有光伏病毒，尽管有教条认为缺乏达菲蛋白， 主要的红细胞(RBC)入侵配体，使非洲人对感染具有免疫力。尽管有越来越多的证据表明 他们增加的负担，几乎对控制PO和PV的关键生物学参数一无所知 在非洲的传播。很大程度上由于缺乏现场诊断和分子工具，PO和PV的研究 大多数非洲国家几乎仅限于横断面患病率调查或便利性调查 从诊所采集样本，没有任何尝试加深对基本传播生物学的了解 以及这些物种的复发模式。这项提议充分利用了该领域的技术进步，包括该领域的技术进步。 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 对非洲PO和PV生物学中的这些基本知识差距进行了强有力的研究。通过社区和 以诊所为基础的监测，我们将确定在喀麦隆Dschang，一个联合地点的PO和PV感染者 非洲所有四种主要人类疟疾的地方性流行，具有最广泛的流行病学 关于中部非洲光伏病毒感染的数据。通过结合人类、媒介和基因组研究，该提案 将提供有关传播生物学(目标1)、复发模式(目标2)的关键信息，对于PV， 克服限制红细胞侵袭的机制的能力(目标3)。填补这些空白将导致 通过定义感染性宿主和 复发对储蓄者的贡献(目标1A、2A和2B)，以及确定目标载体 干预(目标1B)。这项工作将提供对非洲光伏和PO的机制的洞察 在面对针对PF的持续消除努力时证明具有弹性，同时生成工具 (例如，看护点诊断和多样性标记)来跟踪这些物种。总而言之，这些发现将有助于 为复发疟疾制定新的疟疾控制战略。

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.