Program for Resistance, Immunology, Surveillance & Modeling of Malaria in Uganda (PRISM) Renewal

摘要/摘要 疟疾仍然是最重要的全球卫生挑战之一，估计有2.15亿病例和 每年有43.8万人死亡。疟疾对撒哈拉以南非洲的影响不成比例，那里88%的病例 90%的死亡都发生在。最近，控制干预措施的规模急剧增加。 以及减轻整个非洲的疟疾负担。然而，进展并不是一成不变的，事实上也是如此 在负担最重的国家，如乌干达，是最慢的。我们名为“棱镜”的节目已经 总部设在乌干达，代表东非地区国际疟疾英才中心 研究网络。乌干达是高负担国家面临的挑战的象征，在那里， 监测系统不足以评估疟疾负担的趋势或监测#年的影响。 控制干预措施。通过PRISM，我们实施了一个全面的疟疾监测方案 包括在三个地区加强以卫生设施为基础的监测和详细的纵向研究 不同的传输强度。以实验室为基础的补充性研究包括监测 疟疾暴露的抗疟疾药物和杀虫剂耐药性及血清学措施。这些研究已经 极大地提高了我们对乌干达疟疾流行病学和控制影响的了解 干预措施。在这次续签申请中，我们建议继续我们疟疾监测的主要组成部分 工作，但要扩大我们的范围，以解决关于 寄生虫、蚊子媒介和人类宿主。将进行更密集的纵向评估，并 将增加尖端分子研究，以更好地测量感染叮咬的暴露；更敏感 识别血液感染；确定寄生虫、病媒和影响 以及评估这些因素对传染性和传播性的影响。该计划将由三个部分组成 研究项目以综合的方式联系在一起，以最大限度地促进科学发现。研究项目1 (抵抗项目)将使用在多个地点随着时间的推移收集的样本来表征 药物和杀虫剂抗药性的表型和基因标记，并评估这些标记的影响 关于疟疾传播的研究。研究项目2(流行病学项目)将使用队列中的纵向样本 确定决定接种子孢子是否会导致血液建立的因素 影响血液持续时间、密度和临床后果的阶段感染和特征因素 感染阶段。研究项目3(传输项目)将使用队列样本来确定因素 结合配子体的产生和发育，评估人类宿主对蚊子的感染性 媒介，并描述人类感染性宿主的特征。这些高度相关的项目将被实施 在疟疾流行病学不同和人口水平不同的情况下，提供关键的 优化乌干达控制和最终消除疟疾战略所需的信息。

Summary/Abstract Malaria remains one of the most important global health challenges, with an estimated 215 million cases and 438 thousand deaths each year. Malaria disproportionately affects sub-Saharan Africa, where 88% of cases and 90% of deaths occur. There has recently been a dramatic increase in the scale up of control interventions and reduction in the burden of malaria across Africa. However, progress has not been uniform, and in fact has been slowest in countries with the highest burden, such as Uganda. Our program called “PRISM” has been based in Uganda, representing the East African region for the International Centers of Excellence for Malaria Research network. Uganda is emblematic of the challenges faced by high burden countries, where routine surveillance systems are inadequate to assess trends in the burden of malaria or to monitor the impact of control interventions. Through PRISM we have implemented a comprehensive malaria surveillance program including enhanced health facility-based surveillance and detailed longitudinal studies in three regions with differing transmission intensities. Complementary laboratory-based studies include surveillance for markers of antimalarial drug and insecticide resistance and serologic measures of malaria exposure. These studies have greatly improved our understanding of the epidemiology of malaria in Uganda and of the impact of control interventions. In this renewal application we propose to continue key components of our malaria surveillance work, but to expand our scope to address more fundamental questions about interactions between the parasite, mosquito vector, and human host. More intensive longitudinal evaluations will be conducted and cutting edge molecular studies will be added to better measure exposure to infective bites; more sensitively identify bloodstream infections; characterize parasite, vector, and human genetic factors that impact on malaria; and assess impacts of these factors on infectivity and transmission. The program will consist of three research projects linked together in an integrated manner to maximize scientific discovery. Research project 1 (Resistance project) will use samples collected over time at multiple sites to characterize the evolution of phenotypic and genotypic markers of drug and insecticide resistance and assess the impacts of these markers on malaria transmission. Research project 2 (Epidemiology project) will use longitudinal samples from cohorts to characterize factors that determine whether sporozoite inoculation results in the establishment of blood stage infection and characterize factors affecting the duration, density, and clinical consequences of blood stage infections. Research project 3 (Transmission project) will use cohort samples to determine factors associated with gametocyte production and development, evaluate infectivity of the human host to mosquito vectors, and characterize the human infectious reservoir. These highly interrelated projects will be conducted in settings with varied malaria epidemiology and differing population level control intervention to provide critical information needed to optimize strategies for the control and ultimate elimination of malaria in Uganda.