Determinants of malaria transmission by submicroscopic gametocytemia

亚显微配子体血症传播疟疾的决定因素

• 批准号: 9926215
• 负责人: Jessica Lin
• 金额: $ 66.93万
• 依托单位: UNIV OF NORTH CAROLINA CHAPEL HILL
• 依托单位国家: 美国
• 财政年份: 2018
• 资助国家: 美国
• 起止时间: 2018-06-22 至 2023-05-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9926215
• 关键词: Affect; Age; Anopheles gambiae; Antibodies; Antimalarials; Area; Biological Assay; Biological Markers; Blood; Blood capillaries; Characteristics; Clinical; Culicidae; Dermal; Diagnostic tests; Epidemiology; Exposure to; Female; Fertilization; Fostering; Genetic; Genetic Variation; Genotype; Health; Human; Immunoassay; Individual; Infection; Ingestion; Institutes; Integration Host Factors; International; Interruption; Lateral; Lead; Malaria; Measures; Mediating; Membrane; Microscopic; Microscopy; Modeling; Molecular; Natural History; Parasitemia; Parasites; Patients; Persons; Pharmaceutical Preparations; Population; Predictive Value; Public Health Practice; Quantitative Reverse Transcriptase PCR; Resistance; Role; Saliva; Sampling; Seasons; Sex Ratio; Shapes; Skin; Symptoms; Tanzania; Techniques; Testing; Time; Toxic effect; Universities; base; chronic infection; deep sequencing; density; design; evidence base; experience; feeding; field study; genome sequencing; malaria infection; malaria transmission; male; next generation sequencing; novel; novel diagnostics; predictive modeling; sex; targeted treatment; tool; transmission process; treatment strategy; unnecessary treatment; whole genome

ABSTRACT Even as malaria control efforts have achieved great reductions in malaria burden over the last decade, vast numbers of asymptomatic infection exist and present an obstacle to malaria elimination. Most asymptomatic carriers harbor parasites that are detectable by PCR but missed by current rapid diagnostic tests and microscopy. These submicroscopic infections are one rationale for mass drug administration efforts. Yet the role of submicroscopic infections in sustaining transmission is unknown. In fact, the malaria parasites responsible for human to mosquito infection, gametocytes, may not achieve transmissible levels in the majority of submicroscopic infections. We propose that a better understanding of gametocyte-mediated transmission at low densities can lead to the design of better strategies to interrupt parasite transmission. Aim 1 of this proposal will use mosquito feeding assays to define who within the asymptomatic reservoir is infectious to mosquitoes, investigating the role of gametocyte density, sex ratio, and strain diversity in determining transmissibility. We will use direct skin feeding to measure human to mosquito transmission, considered a truer, more sensitive measure of human infectiousness than more commonly used membrane feeding assays. Aim 2 will determine the propensity for submicroscopic infections to persist and develop infective gametocytes over time. In these two aims, next generation sequencing techniques will be used to distinguish individual gametocyte strains to better understand how the composition of mixed gametocyte populations within individuals changes over time and affects transmission, and whether intensive control efforts are selecting for parasite strains that are able to persist at low densities without causing symptoms. This information is crucial to understanding what factors sustain transmission from submicroscopic gametocyte carriers even as overall transmission wans. Finally, Aim 3 deploys a field-relevant novel diagnostic test that has the potential to reshape malaria elimination strategies. We hypothesize that the sensitivity of Gam-RDT, a lateral flow immunoassay that detects a newly discovered gametocyte marker in saliva, approximates the gametocyte density at which transmission occurs, making it a valuable field tool for identifying parasite carriers who make up the infectious reservoir. We will conduct our study in Bagamoyo, Tanzania, an area where, although malaria cases have decreased over the last decade, up to ~45% of schoolchildren continue to have asymptomatic parasitemia detectable by highly sensitive PCR. Our team of experienced clinical trialists, leading malaria entomologists, and international experts in malaria epidemiology and genetic diversity will establish the evidence base for how malaria transmission from submicroscopic gametocyte carriers occurs in the face of intensive control efforts that have successfully reduced the global malaria burden, but will likely not be enough to eradicate this age-old human parasite.

抽象的 尽管疟疾控制工作在过去十年中大大减少了疟疾负担，但 大量无症状感染者的存在给消除疟疾带来了障碍。大多数无症状 携带者体内含有可通过 PCR 检测到的寄生虫，但目前的快速诊断测试无法检测到， 显微镜。这些亚显微感染是大规模药物管理工作的理由之一。然而 亚显微感染在维持传播中的作用尚不清楚。事实上，疟原虫 负责人与蚊子感染的配子细胞，在大多数情况下可能无法达到可传播的水平 亚显微感染。我们建议更好地理解配子体介导的传播 低密度可以设计出更好的策略来中断寄生虫传播。这个目标1 该提案将使用蚊子喂养检测来确定无症状宿主中谁具有传染性 蚊子，研究配子体密度、性别比例和品系多样性在决定中的作用 传播性。我们将使用直接皮肤喂养来测量人与蚊子的传播，被认为是更真实的， 比更常用的膜喂养测定更灵敏地测量人类传染性。目标2 将确定亚显微感染持续存在并发展感染性配子体的倾向 时间。在这两个目标中，下一代测序技术将用于区分个体 配子体菌株，以更好地了解混合配子体群体的组成如何 个体随着时间的推移而变化并影响传播，以及强化控制努力是否正在选择 能够以低密度持续存在而不引起症状的寄生虫菌株。这些信息对于 了解哪些因素维持亚显微配子体携带者的传播，甚至总体而言 传输湾。最后，Aim 3 部署了一种与现场相关的新型诊断测试，该测试有可能 重塑消除疟疾战略。我们假设 Gam-RDT（侧流）的敏感性 检测唾液中新发现的配子体标记的免疫测定，近似配子体 传播发生的密度，使其成为识别寄生虫携带者的宝贵现场工具。 上升到传染源。我们将在坦桑尼亚的巴加莫约进行研究，该地区虽然疟疾 过去十年中病例有所减少，高达约 45% 的学童仍然无症状 可通过高灵敏 PCR 检测到寄生虫血症。我们的团队由经验丰富的临床试验人员组成，在疟疾领域处于领先地位 昆虫学家以及疟疾流行病学和遗传多样性方面的国际专家将建立 亚显微配子体携带者如何传播疟疾的证据基础 密集的控制努力已成功减轻了全球疟疾负担，但可能还不够 根除这种古老的人类寄生虫。