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 即使在过去的十年中，随着疟疾的控制努力大大减轻了疟疾负担， 存在无症状感染的数量，并带来消除疟疾的障碍。最无症状的 运营商港口寄生虫可通过PCR检测，但由于当前的快速诊断测试而错过 显微镜。这些亚镜下感染是大众药物管理工作的一个理由。但是 亚镜下感染在维持传播中的作用尚不清楚。实际上，疟疾寄生虫 对人类感染的负责，配子细胞可能无法达到多数的传播水平 亚镜下感染。我们建议更好地理解对配子细胞介导的传播 低密度可以导致设计更好的策略来中断寄生虫传播。目标1 提案将使用蚊子喂养测定法来定义谁在无症状的储层中具有感染力 蚊子，研究配子细胞密度，性别比和应变多样性在确定中的作用 传播性。我们将使用直接的皮肤喂养来测量人类到蚊子传播，被认为是一种更真实的， 与更常用的膜进食测定法相比，对人类感染性的衡量更敏感。目标2 将确定亚镜下感染持续和发展感染性配子细胞的倾向 时间。在这两个目标中，下一代测序技术将用于区分个体 配子细胞菌株，以更好地了解混合子同子体种群的成分 个人会随着时间的推移而变化并影响传播，以及是否正在选择强化控制工作 寄生虫菌株能够在低密度下持续而不会引起症状。此信息对 了解哪些因素可以维持从亚微镜携带者的传播，即使是总体上 变速箱。最后，AIM 3部署了与现场相关的小说诊断测试，该测试有可能 重塑疟疾消除策略。我们假设GAM-RDT的灵敏度，横向流动 检测到唾液中新发现的配子细胞标记的免疫测定值近似Gametocyte 发生传输的密度，使其成为识别制造的寄生虫载体的宝贵现场工具 向上升高感染性水库。我们将在坦桑尼亚的Bagamoyo进行研究，尽管疟疾 在过去的十年中，案件有所下降，多达约45％的学童继续无症状 高度敏感的PCR可检测到寄生虫血症。我们经验丰富的临床试验者团队，领导疟疾 昆虫学家以及疟疾流行病学和遗传多样性的国际专家将建立 证据表明如何在面对微观的配子体载体传播中传播疟疾 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 消除这个古老的人类寄生虫。