Unravelling disease tolerance and host resistance in afebrile P. falciparum infections: a prospective study in Mozambican adults

摘要 无症状恶性疟原虫(PF)感染削弱了受影响人口的健康，而 代表了寄生虫传播的隐藏来源，可能会危及消除努力。缺乏 在处理这种无症状水库的最佳策略上达成了共识，部分原因是知识贫乏 这些亚临床感染背后的生物学机制。莫桑比克的初步结果 研究表明，快速诊断试验检测出感染肺泡炎的不发烧成人可进展为发烧(10%)， 清除感染(20%)，并稳定在低密度(50%)或高密度(20%)寄生虫病。我们 假设这四个主要轨迹是由针对PF变异抗原的抗体驱动的，编码为 通过var基因家族，并在感染的红细胞表面表达，从而清除 感染，除非寄生虫形成免疫逃避机制，并通过将耐受因素降至最低 寄生虫诱导的病理和维持宿主的同源稳定。首要目标是识别关键 生物因素维持无热性疟疾感染，该项目将建立一个无热性队列 莫桑比克成年人在一个月内进行了跟踪调查，以确定哪些受试者可以减少病原体载量和 最终清除感染，那些将感染保持在高密度和无热性水平(耐受性)的人， 以及那些未能建立疾病耐受性并进展为发烧的人。我们将量化流通和 总寄生虫生物量，并使用下一代测序在后续行动中识别新感染。 来自低寄生虫密度和高寄生虫密度的个人的临床样本将被用于测试 无热性肺炎的寄生虫学轨迹与宿主抗红细胞抗体免疫相关 参与细胞黏附和免疫逃避的表面抗原和PF var基因的转录(目的 1)。飞行时间细胞术和全球质谱仪将应用于无热病患者的临床样本 寄生虫密度高的个体(耐受)和进展到发烧(不耐受)的个体以识别 参与炎症、组织损伤调节的白细胞群和代谢途径 以及在非发热水平支持宿主-寄生虫关系的正常血糖(目标2)。我们将对这些进行验证 使用从乌干达儿童和成人队列中获得的一组独立样本的结果 疟疾发病率和寄生虫流行的纵向测量。该项目将有助于 在Manhiça卫生研究中心发展科学能力，并为未来创建一个样本库 非热性疟疾感染期间宿主和寄生虫相互作用的调查(目标3)。预期中的 该项目的成果是确定了无热性肺炎感染的关键分子驱动因素，以便更好地 了解这些感染在不同传播环境中的相关性可能需要 针对具体情况的控制方法，以及开发实现消毒的新工具 增强免疫力，增强疾病耐受性。

ABSTRACT Asymptomatic Plasmodium falciparum (Pf) infections debilitate the health of affected population while representing a hidden source of parasite transmission that can compromise elimination efforts. The lack of consensus on the best strategy to deal with this asymptomatic reservoir is partly due to the poor knowledge on the biological mechanisms underlying these subclinical infections. Preliminary results in Mozambique show that afebrile adults with a Pf infection detected by rapid diagnostic tests can progress to fever (10%), clear the infection (20%) and stabilize at low-density (50%) or high-density (20%) parasitemias. We hypothesize that these four main trajectories are driven by antibodies against Pf variant antigens, codified by the var gene family and expressed on the surface of infected erythrocytes, which would clear the infection unless the parasites develop immune evasion mechanisms, and by tolerance factors that minimize parasite-induced pathology and sustains host homeostasis.With the overarching goal of identifying key biological factors sustaining afebrile malaria infections, this project will establish a cohort of afebrile Mozambican adults followed during one month to identify subjects who can reduce pathogen load and eventually clear the infection, those who maintain infections at high-density and afebrile levels (tolerant), and those who fail to establish disease tolerance and progress to fever. We will quantify circulating and overall parasite biomass, and identify new infections during follow-up using next-generation sequencing. Clinical samples from individuals with low and high parasite densities will be used to test whether parasitological trajectories of afebrile Pf infections correlate with host antibody immunity against erythrocyte surface antigens and the transcription of Pf var genes involved in cytoadhesion and immune evasion (Aim 1). Cytometry by time of flight and global mass spectrometry will be applied on clinical samples from afebrile individuals with high parasite densities (tolerant) and those progressing to fever (non-tolerant) to identify leukocyte populations and metabolic pathways involved in the regulation of inflammation, tissue damage and normoglycemia that support host-parasite relationships at afebrile levels (Aim 2). We will validate these results using an independent set of samples obtained from a Ugandan cohort of children and adults with longitudinal measurement of malaria incidence and parasite prevalence. This project will contribute to develop scientific capacity at the Manhiça Health Research Center and create a sample repository for future investigations on host and parasite interactions during afebrile malaria infections (Aim 3). The expected outcome of this project is the identification of key molecular drivers of afebrile Pf infections for a better understanding of the relevance of these infections in different transmission setting which may require context-specific control approaches, as well as for the development of new tools to achieve sterilizing immunity and enhance disease tolerance.