Defining physiological correlates of the human malaria infectious reservoir

 描述(申请人提供)：尽管经过几十年的公共卫生努力，疟疾仍然是全球主要死亡原因之一，并影响到全球约一半的人口。许多疟疾流行国家最近承诺消灭疟疾，这标志着公共卫生政策的转变，从旨在控制疾病负担的计划，转向强调减少人类最致命的疟疾寄生虫恶性疟原虫传播的计划。然而，人类血液中只有很小一部分疟疾寄生虫能够感染蚊子，而且这些传播阶段仍然没有得到充分的研究，因为它们不会致病，很难用传统方法检测到。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，这一教条是错误的，感染低密度疟疾的人实际上可以非常有效地传播给蚊子。此外，我们还证明，与来自静脉血样的血餐相比，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，即可传播疟疾寄生虫阶段聚集在蚊子最有效找到它们的皮肤下。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不准确。皮下传播阶段的聚集性可能大大有助于疟疾寄生虫在人群中惊人有效的传播。在这里，我们的目标是使用马拉维致命疟疾病例的一组独特的尸检和布基纳法索的蚊子喂养实验来直接验证这一假设。我们将使用组织学和一种新的纳米串平台来分析我们的人类样本，这是一种为恶性疟原虫无性和传播阶段量身定做的高度敏感的表达。同时，将确定不同人体隔间(皮肤和静脉血)的蚊子喂食结果。总而言之，这项跨学科的研究将使用现代工具来检验长期而有力的假设。因此，它将为在人口一级准确预测疟疾传播率奠定基础，以便为实现消除疟疾的公共卫生干预措施和时间表提供信息。如果我们确实观察到配子细胞在皮肤下聚集，我们的研究将形成系统机制研究的起点，并可能导致新的传播阻断干预措施。

 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.