The Immunologic Impact of In Utero Malaria Exposure and Prenatal Chemoprevention

项目摘要/摘要自上级授予后未更改 据估计，怀孕期间的疟疾影响了1200多万妇女，导致大量 不良分娩结局包括低出生体重、死产、产妇贫血和胎儿宫内发育。 限制。目前唯一可用的疟疾疫苗受到儿童免疫原性差的限制。 生活在疟疾流行的环境中。据报道，患有胎盘性疟疾的母亲所生的孩子患有 在生命的头几年，疟疾的风险增加。最近的研究揭示了耐人寻味的证据表明胎儿 对疟疾抗原的耐受性，暗示了这种联系的潜在免疫学机制。更改后的 出生后的先天和获得性免疫反应在宫内疟疾后被证明 曝光。在胎盘脐带血中描述了一种耐受性或免疫调节性T细胞表型 感染疟疾的婴儿。此外，一些研究发现，患有胎盘的母亲所生的婴儿 疟疾减少了对儿童常规疫苗接种的反应。因此，预防胎盘 通过加强化学预防来诱导疟疾免疫耐受有可能增强 儿童早期的纵向疟疾特异性免疫和全球免疫。 这项K23提案的目标是检验这样一种假设，即在子宫内感染疟疾会导致耐受性 增强的产前疟疾抑制的胎儿疟疾特异性和全球免疫反应 化学预防。我们将通过以下途径确定宫内疟疾暴露的免疫学后果 以下三个目标：1)确定宫内疟疾暴露和产前化学预防对 儿童早期疟疾特异性T细胞免疫反应。2)确定宫内疟疾的效果 暴露和产前化学预防对疟疾感染早期先天免疫反应的影响 3)评估宫内疟疾暴露对常规免疫反应的影响 接种疫苗。为了实现这些目标，我们将利用现有的基础设施和来自一组 一对母婴登记参加正在进行的基于青蒿素的高效随机临床试验 乌干达的产前疟疾化学预防。本申请中建议的研究将建立在 候选人的初步发现表明脐带血免疫调节反应的发展 在宫内暴露于疟疾的婴儿中。 这位候选人的职业目标是破译感染传染病的生物学基础 并将这些发现应用于应对全球卫生挑战。在此K23应用程序中， 候选人概述了一份详细的研究和职业发展计划，该计划是根据她的职业目标量身定做的。 她将接受国际合作的高级免疫学研究技术方面的额外培训 研究和生物统计分析。通过评估目标产生的数据和技术培训 将作为建立评估疟疾宿主-病原体相互作用的R01提交的框架。

Project Summary/Abstract Unchanged since Parent Grant Malaria in pregnancy is estimated to affect greater than 12 million women leading to a multitude of adverse birth outcomes including low-birth weight, stillbirths, maternal anemia, and intrauterine growth restriction. The only currently available malaria vaccine has been limited by poor immunogenicity in children living in malaria-endemic settings. Children born to mothers with placental malaria have been reported to have an increased risk of malaria in the first years of life. Recent studies have revealed intriguing evidence of fetal tolerance to malaria antigens, suggesting a potential immunologic mechanism for this association. Altered innate and adaptive immune responses after birth have been demonstrated following in utero malaria exposure. A tolerant, or immunoregulatory, T cell phenotype has been described in the cord blood of placental malaria-exposed infants. Additionally, some studies have found that infants born to mothers with placental malaria have decreased response to routine childhood vaccinations. Therefore, prevention of placental malaria-induced immune tolerance through enhanced chemoprevention has the potential to augment longitudinal malaria-specific and global immunity during early childhood. The goal of this K23 proposal is to test the hypothesis that in utero malaria infection induces tolerogenic fetal malaria-specific and global immune responses that are inhibited by enhanced prenatal malaria chemoprevention. We will determine the immunologic consequences of in utero malaria exposure through the following three aims: 1) To determine the effect of in utero malaria exposure and prenatal chemoprevention on malaria-specific T-cell immune responses in early childhood. 2) To determine the effect of in utero malaria exposure and prenatal chemoprevention on innate immune responses during malaria infection in early childhood 3) To assess the impact of in utero malaria exposure on the immune response to routine vaccination. To achieve these aims we will leverage existing infrastructure and samples from a cohort of mother-infant pairs enrolled in an ongoing randomized clinical trial of highly effective artemisinin-based prenatal malaria chemoprevention in Uganda. The studies proposed in this application will build on the candidate’s preliminary findings suggesting the development of cord blood immunoregulatory responses among in utero malaria-exposed infants. The candidate’s career goal is to decipher the biologic underpinnings of infectious diseases that afflict the impoverished, and to apply these findings to address global health challenges. In this K23 application, the candidate has outlined a detailed research and career development plan tailored to match her career goals. She will gain additional training in advanced techniques of immunology research, international collaborative research, and biostatistical analysis. Data and technical training generated through the evaluation of the aims will serve as a framework to build a R01 submission evaluating host-pathogen interactions of malaria.