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

揭示无发热恶性疟原虫感染的疾病耐受性和宿主抵抗力：莫桑比克成人的前瞻性研究

• 批准号: 10410393
• 负责人: Pedro AIDE
• 金额: $ 13.63万
• 依托单位: FUNDACAO MANHICA
• 依托单位国家: 美国
• 财政年份: 2020
• 资助国家: 美国
• 起止时间: 2020-06-01 至 2025-05-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10410393
• 关键词: Adult; Affect; Antibodies; Antibody Response; Antibody-mediated protection; Antigens; Biological; Biological Assay; Biological Factors; Biomass; Child; Chronic; Clinical; Consensus; Cytometry; Data; Detection; Development; Diagnostic tests; Disease; Down-Regulation; Epidemiology; Equilibrium; Erythrocyte Membrane; Erythrocytes; Failure; Fever; Flow Cytometry; Future; Gene Expression Profile; Gene Family; Genes; Genetic Transcription; Genotype; Goals; Health; Heterogeneity; Homeostasis; Host resistance; Host-Parasite Relations; Immune; Immune Evasion; Immune System Diseases; Immune response; Immunity; Incidence; Individual; Infection; Inflammation; Inflammatory; Inflammatory Response; Investigation; Knowledge; Leukocytes; Malaria; Mass Spectrum Analysis; Measurement; Mediating; Membrane Proteins; Metabolic; Metabolic Pathway; Microscopy; Molecular; Molecular Biology; Molecular Immunology; Mozambique; Outcome; Parasitemia; Parasites; Pathogenicity; Pathology; Pathway interactions; Plasmodium falciparum; Plasmodium falciparum erythrocyte membrane protein 1; Population; Prevalence; Prospective Studies; Rapid diagnostics; Regulation; Research; Role; Sampling; Severities; Source; Surface; Surface Antigens; Symptoms; Testing; Time; Tissues; Up-Regulation; Variant; Work; chronic infection; cohort; density; evidence base; follow-up; immune resistance; malaria infection; next generation sequencing; novel strategies; pathogen; preservation; pressure; repository; tool; transmission process; γδ T cells

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.

抽象的 不对称疟原虫恶性疟原虫（PF）感染使受影响人群的健康衰弱，而 代表隐藏的寄生虫传播来源，可以损害消除努力。缺乏 在处理这种无症状水库的最佳策略上达成共识，部分原因是知识不足 关于这些亚临床感染的生物学机制。莫桑比克的初步结果 表明通过快速诊断测试检测到具有PF感染的Afebrile成年人可以发烧（10％）， 清除感染（20％），并以低密度（50％）或高密度（20％）寄生虫稳定。我们 假设这四个主要轨迹是由针对PF变体抗原的抗体驱动的， 由var基因家族并在感染的红细胞表面表达，这将清除 除非寄生虫产生免疫进化机制，否 寄生虫引起的病理学和自杀宿主体内平衡。以识别密钥的总体目标 维持Afebrile疟疾感染的生物学因素，该项目将建立一系列afebrile 莫桑比克成年人在一个月内遵循，以确定可以减少病原体负荷和的受试者 最终清除感染，那些将感染保持高密度和Afebrile水平（耐受）的人， 那些未能建立疾病耐受性并发烧的人。我们将量化循环和 总体寄生虫生物量，并在随访期间使用下一代测序确定新的感染。 来自低寄生虫密度和高寄生虫密度的个体的临床样本将用于测试是否是否 Afebrile PF感染的寄生轨迹与宿主抗体免疫相关 表面抗原和参与细胞粘附和免疫进化的PF VAR基因的转录（AIM 1）。通过飞行时间和全球质谱法进行的细胞仪将应用于AFEBRILE的临床样本 具有高寄生虫密度（耐受性）的个体和发烧的人（不耐受） 白细胞种群和代谢途径涉及感染调节，组织损伤 以及支持在Afebrile层面的宿主 - 寄生虫关系的正常血糖（AIM 2）。我们将验证这些 结果使用从乌干达的儿童和成人队获得的独立样本集 疟疾入射和寄生虫患病率的纵向测量。这个项目将有助于 在Manhiça健康研究中心开发科学能力，并为未来创建样本存储库 在Afebrile疟疾感染期间对宿主和寄生虫相互作用的调查（AIM 3）。预期 该项目的结果是确定Afebrile PF感染的关键分子驱动因素 了解这些感染在不同传输环境中的相关性，这可能需要 特定于上下文的控制方法以及开发新工具以实现消毒 免疫并增强疾病的耐受性。