Enteric Pathogen Force of Infection among Children using Serology

肠道病原体感染是全球疾病负担的主要原因， 低资源环境中的儿童。基于粪便的PCR方法大大提高了我们测量 肠道感染，但收集粪便的挑战和需要近乎连续的监测，以检测许多 全球重要的病原体阻碍了在大规模监测中更广泛的使用。规模庞大，人口众多- 基于调查的现在定期收集血液，以监测艾滋病毒、疟疾等疾病的传播和负担 和登革热。对这些调查中收集的血液进行更广泛的多重检测代表了一种新的 测量肠道病原体传播和负担的机会。基于抗体的措施可以补充 基于粪便的PCR检测，因为抗体反应在感染后数月内仍保持升高， 在不频繁测量的研究中提供更多信息。我们的团队开发了多重珠 测定免疫球蛋白G（IgG）对多种肠道病原体的反应的测定。在初步研究中， 已经表明IgG水平可用于测量肠道病原体之间传播的异质性， 人口。我们还表明，结果推广到跨类群的病原体。在本申请中，我们 我建议完成一系列研究，解决关键的下一步，以推进肠道感染的血清流行病学。 低资源环境中的病原体。我们将在厄瓜多尔进行纵向出生队列研究， 分辨率，多重粪便PCR感染与纵向，多重IgG和伊加测量。我们的17- 该研究中心一年的研究历史记录了不同地区肠道病原体感染的实质性变化。 城乡梯度，使其成为研究的理想环境。该队列将招募来自三个国家的600名儿童 在农村-城市梯度的地点，并经常测量他们从出生到24个月。关于Luminex 平台，我们将对15种肠道病原体的多重PCR评估与IgG和伊加评估进行配对， 多重微珠检测，包括7种肠道病原体的抗原：空肠弯曲杆菌、肠致病性 大肠杆菌、肠道沙门氏菌、贾第鞭毛虫、微小隐孢子虫、溶组织内阿米巴和 诺如病毒在目标1中，我们将使用基于分子和抗体的措施来研究肠道感染力 病原体在城乡之间的梯度分布。这将是第一次广泛的比较， 预防肠道感染的血清流行病学措施。在目标2中，我们将评估肠道病原体 感染力的现状模型，以人口为基础，横断面血清学调查， 地区，并将基准的横截面估计对那些获得的同时纵向 study.在目标3中，我们将研究7种病原体感染后的IgG和伊加动力学，并开发 模型，以准确地预测最近的感染和发病率从抗体水平测量的横截面 血清学调查。这些目标的完成将导致具有以下特征的可推广的血清流行病学方法： 有可能改变低资源环境中肠道病原体传播和负担的测量。

Enteric pathogen infections are a leading cause of the global disease burden, with the largest burden among children in low-resource settings. Stool-based PCR methods have dramatically improved our ability to measure enteric infections, but the challenge of collecting stool and need for near-continuous monitoring to detect many globally important pathogens has thwarted broader use in large-scale surveillance. Large-scale, population- based surveys now regularly collect blood to monitor transmission and burden of diseases such as HIV, malaria and dengue. Broader testing of blood collected in such surveys with multiplex assays represents a new opportunity to measure enteric pathogen transmission and burden. Antibody-based measures could complement stool-based PCR testing because antibody responses remain elevated for many months after infection, thus providing more information in studies with infrequent measurements. Our team has developed multiplex bead assays that measure immunoglobulin G (IgG) response to diverse enteric pathogens. In preliminary studies we have shown that IgG levels can be used to measure heterogeneity in enteric pathogen transmission between populations. We have also shown the results generalize to pathogens that span taxa. In this application, we propose to complete a series of studies that address key next steps to advance the seroepidemiology of enteric pathogens in low-resource settings. We will conduct a longitudinal birth cohort in Ecuador that pairs high resolution, multiplex stool-based PCR infection with longitudinal, multiplex IgG and IgA measurements. Our 17- year research history at the site has documented substantial variation in enteric pathogen infection across a rural-urban gradient, making it an ideal setting for the research. The cohort will enroll 600 children from three sites across a rural-urban gradient, and measure them frequently from birth to 24 months. On the Luminex platform, we will pair multiplex PCR assessment for 15 enteric pathogens with IgG and IgA assessment in a multiplex bead assay that includes antigens to 7 enteric pathogens: Campylobacter jejuni, enterotoxigenic Escherichia coli, Salmonella enterica, Giardia duodenalis, Cryptosporidium parvum, Entamoeba histolytica, and norovirus. In Aim 1, we will use molecular and antibody-based measures to study force of infection of the enteric pathogens across a rural-urban gradient. This will represent the first broad-based comparison of seroepidemiologic measures against patent infection for enterics. In Aim 2, we will estimate enteric pathogen force of infection by applying current-status models to population-based, cross-sectional serology surveys in the region, and will benchmark the cross-sectional estimates against those obtained in the concurrent longitudinal study. In Aim 3, we will study IgG and IgA kinetics following infection for each of the 7 pathogens, and develop models to accurately predict recent infections and incidence from antibody levels measured in cross-sectional serology surveys. Completion of these aims will result in generalizable seroepidemiologic methods that have the potential to transform measurement of enteric pathogen transmission and burden in low-resource settings.