Defining physiological correlates of the human malaria infectious reservoir

定义人类疟疾传染源的生理相关性

• 批准号: 9228305
• 负责人: Dyann F Wirth
• 金额: $ 20.19万
• 依托单位: HARVARD SCHOOL OF PUBLIC HEALTH
• 依托单位国家: 美国
• 财政年份: 2016
• 资助国家: 美国
• 起止时间: 2016-02-17 至 2019-01-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9228305
• 关键词: Address; Affect; Anopheles Genus; Automobile Driving; Autopsy; Biological Assay; Blood; Blood capillaries; Blood specimen; Bone Marrow; Brain; Burkina Faso; Cause of Death; Cessation of life; Childhood; Clinical; Complex; Country; Culicidae; Data; Development; Disease; Epidemiology; Erythrocytes; Female; Fingers; Foundations; Genetic Transcription; Health Policy; Histologic; Histology; Human; Individual; Infection; Injection of therapeutic agent; Interdisciplinary Study; Intervention; Lead; Malaria; Malawi; Measures; Methods; Microscopic; Microscopy; Modeling; Modernization; Molecular; Outcome; Parasites; Parasitic Diseases; Participant; Pathway interactions; Physiological; Plasmodium falciparum; Policies; Population; Population Study; Positioning Attribute; Public Health; Recruitment Activity; Risk; Sampling; Series; Skin; Systematic Bias; Techniques; Testing; TimeLine; Tissues; Treatment Efficacy; Venous; Venous blood sampling; Virulent; asexual; base; burden of illness; capillary; cohort; comparative; density; design; experimental study; feeding; human disease; improved; insight; malaria infection; malaria transmission; mathematical model; nano-string; novel; programs; public health intervention; public health relevance; standard measure; tool; transmission process

 DESCRIPTION (provided by applicant): Malaria remains one of the leading causes of death worldwide and affects about half the global population, despite decades of public health efforts. The recent commitment to eliminate malaria by many endemic countries marks a shift in public health policy away from programs aimed at controlling disease burden towards one that emphasizes reducing transmission of the most virulent human malaria parasite, Plasmodium falciparum. Only a very small fraction of malaria parasites within human blood are able to infect mosquitoes, however, and these transmission stages have remained under-studied because they do not cause disease and are difficult to detect by conventional methods. Because malaria transmission stages are rarely detected, it has been assumed that only a small fraction of malaria-infected individuals are capable of infecting mosquitoes. Our recent preliminary data suggest that this dogma is wrong, however, and that people with low-density malaria infections can in fact transmit to mosquitoes very efficiently. In addition, we demonstrated that blood meals directly from the skin of an infected participant more commonly result in mosquito infection compared to blood meals from venous blood samples. This led to our hypothesis that transmissible malaria parasite stages cluster under the skin where mosquitoes can find them most effectively. If this hypothesis is correct, all previous analyses of infectiousness based on venous blood are not accurate. The clustering of transmission stages under the skin may contribute considerably to the phenomenally efficient spread of malaria parasites in populations. Here we aim to test this hypothesis directly using a unique set of autopsies from fatal malaria cases in Malawi and using mosquito-feeding experiments in Burkina Faso. We will analyze our human samples using both histology and a new Nanostring platform, a highly sensitive expression tailored for P. falciparum asexual and transmission stages. In parallel mosquito feeding outcome from the different human compartments sampled (skin and venous blood) will be determined. Together, this interdisciplinary study will test long-standing and powerful hypothesis using modern tools. As such it will lay the foundation for accurate predictions of malaria transmissibility at a population level that can inform public health interventions and timelines to achieve malaria elimination. If we indeed observe that gametocytes cluster under the skin, our study will form the starting point for systematic mechanistic studies and may lead to novel transmission- blocking interventions.

 描述（由申请人提供）：疟疾仍然是世界范围内的主要死因之一，影响了全球约一半的人口，尽管几十年的公共卫生努力。许多疟疾流行国家最近承诺消除疟疾，这标志着公共卫生政策从旨在控制疾病负担的计划转向强调减少最致命的人类疟疾寄生虫恶性疟原虫的传播。然而，人类血液中只有很小一部分疟原虫能够感染蚊子，这些传播阶段仍然没有得到充分研究，因为它们不会引起疾病，并且难以通过常规方法检测。由于疟疾传播阶段很少被检测到，人们一直认为只有一小部分疟疾感染者能够感染蚊子。然而，我们最近的初步数据表明，这种教条是错误的，低密度疟疾感染的人实际上可以非常有效地传播给蚊子。此外，我们还证明，与静脉血样相比，直接来自受感染参与者皮肤的血餐更容易导致蚊子感染。这导致了我们的假设，即传染性疟疾寄生虫阶段聚集在皮肤下，蚊子可以最有效地找到它们。如果这一假设是正确的，那么之前所有基于静脉血的传染性分析都是不准确的。皮肤下传播阶段的聚集可能对疟疾寄生虫在人群中的高效传播有相当大的贡献。在这里，我们的目标是直接使用马拉维致命疟疾病例的一组独特的尸体解剖和布基纳法索的蚊子喂养实验来验证这一假设。我们将使用组织学和新的Nanostring平台分析我们的人类样本，Nanostring平台是一种针对恶性疟原虫无性和传播阶段量身定制的高度敏感的表达。平行地，将确定来自不同人类隔室采样（皮肤和静脉血）的蚊子进食结果。这项跨学科的研究将使用现代工具来测试长期存在的强大假设。因此，它将为准确预测疟疾在人口水平上的传播奠定基础，从而为公共卫生干预措施和实现消除疟疾的时间表提供信息。如果我们确实观察到配子体在皮肤下聚集，我们的研究将成为系统机制研究的起点，并可能导致新的传播阻断干预措施。

项目成果

Plasmodium falciparum Gametocyte Density and Infectivity in Peripheral Blood and Skin Tissue of Naturally Infected Parasite Carriers in Burkina Faso.

• DOI: 10.1093/infdis/jiz680
• 发表时间: 2021-05-28
• 期刊: The Journal of infectious diseases
• 作者: Meibalan E;Barry A;Gibbins MP;Awandu S;Meerstein-Kessel L;Achcar F;Bopp S;Moxon C;Diarra A;Debe S;Ouédraogo N;Barry-Some I;Badoum ES;Fagnima T;Lanke K;Gonçalves BP;Bradley J;Wirth D;Drakeley C;Guelbeogo WM;Tiono AB;Marti M;Bousema T
• 通讯作者: Bousema T