Epidemiology Project

摘要 撒哈拉以南非洲恶性疟疾的负担仍然高得令人无法接受，尽管在#年取得了重大进展。 过去15年的疟疾控制。提高了预测哪些干预措施组合的能力 最有可能带来最大的好处，准确地评估它们的影响将是巨大的 利益。然而，目前的预测受到诸如关系描述不佳等差距的限制 暴露于感染了子孢子的蚊子、血液期感染率和 感染的临床后果，包括抗疟疾免疫的关键影响。在这个项目中，我们将 利用对昆虫学、寄生虫学、人类基因组和临床数据的独特访问 乌干达不同地区的密集队列。重要的是，将在发生变化的地点建立队列 在社区，有计划的干预措施。使用队列数据，我们将量化环境和 宿主因素对感染的建立和维持，并定义宿主所依据的血清学特征 免疫力是一个关键的宿主因素，可以测量。这些努力的核心将是我们发现、区分、 随着时间的推移，跟踪个体血液中不同基因的寄生虫，使我们能够准确地测量 感染力(血液期感染的获得率)，以跟踪这些感染的轨迹 并将这些指标与昆虫学、流行病学和临床结果数据联系起来。我们会 然后结合这些个体水平的关系来表征它们的流行病学后果和模型 干预措施在人口层面的影响。本研究有两个目的：1)表征影响因素 在乌干达不同地点进行深入研究的队列中确定感染疟疾的力量。 我们将得出生活在疟疾流行地区的个体暴露于子孢子的估计，基因 寄生虫感染它们，得出感染力的衡量标准，并评估人类基因 使用全基因组方法对所有队列成员进行多态分析。有了这些数据，我们将确定 子孢子暴露与感染力的关系，这是预测影响的关键关系 病媒控制干预措施，并评估宿主因素的影响，包括遗传、年龄和最近 这段关系的曝光率发生了变化。2)确定影响持续时间、密度和 乌干达血液期疟疾感染的临床后果。用定量聚合酶链式反应和寄生虫 基因分型数据，我们将确定宿主因素的影响，如遗传，年龄和先前接触 血液期免疫力和贫血。我们将确定这些关系如何在不同的 流行病学环境，包括社区干预措施变化之前和之后。此外，我们还将 通过测量对恶性疟原虫的反应来确定与血液阶段免疫相关的血清学特征 利用基因芯片分析蛋白质。

Abstract The burden of falciparum malaria in sub-Saharan Africa remains unacceptably high despite significant gains in malaria control over the last 15 years. An improved ability to both predict which combinations of interventions are most likely to have the greatest benefit and to accurately evaluate their effects would be of enormous benefit. However, predictions are currently limited by gaps such as poor characterization of relationships between exposure to sporozoite-infected mosquitoes, rates of establishment of blood stage infection, and the clinical consequences of infection, including the crucial impact of antimalarial immunity. In this project, we will take advantage of unique access to linked entomologic, parasitologic, human genomic, and clinical data from intensive cohorts in different regions of Uganda. Importantly, cohorts will be established in sites where changes in community interventions are planned. Using cohort data, we will quantify the impact of environmental and host factors on the establishment and maintenance of infection, and define a serologic profile by which host immunity, a key host factor, can be measured. Central to these efforts will be our ability to detect, distinguish, and follow genetically distinct parasites in the blood of individuals over time, allowing us to accurately measure the force of infection (rate of acquisition of blood stage infections), to follow the trajectory of these infections within a host, and to relate these metrics to entomologic, epidemiologic, and clinical outcome data. We will then integrate these individual-level relationships to characterize their epidemiologic consequences and model the impact of interventions at the population level. This study has 2 aims: 1) To characterize factors determining the malarial force of infection in intensively studied cohorts at different sites in Uganda. We will derive estimates of sporozoite exposure in individuals living in malaria endemic areas, genotype parasites infecting them to derive measures of the force of infection, and evaluate human genetic polymorphisms in all cohort members using a genome-wide approach. With these data, we will determine the relationship between sporozoite exposure and the force of infection, a key relationship in predicting the effect of vector control interventions, and assess the impact of host factors including genetics, age, and recent changes in exposure on this relationship. 2) To determine factors affecting the duration, density, and clinical consequences of blood stage malaria infection in Uganda. Using quantitative PCR and parasite genotyping data, we will determine the impact of host factors such as genetics, age, and prior exposure on blood stage immunity as well as anemia. We will determine how these relationships vary in different epidemiologic settings, including before and after changes in communitywide interventions. In addition, we will define a serologic profile associated with blood stage immunity by measuring responses to P. falciparum proteins by microarray.