The Immunologic Impact of In Utero Malaria Exposure and Prenatal Chemoprevention

项目总结/摘要 据估计，怀孕期间的疟疾影响了1 200多万妇女， 不良出生结局，包括低出生体重、死产、母体贫血和宫内发育 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，患有胎盘型疟疾的母亲所生的儿童 在生命的最初几年里患疟疾的风险增加。最近的研究揭示了有趣的证据， 对疟疾抗原的耐受性，提示了这种关联的潜在免疫机制。改变 出生后的先天性和适应性免疫反应已经在子宫内疟疾后得到证实 exposure.一种耐受性或免疫调节性T细胞表型已经在胎盘母细胞瘤的脐带血中被描述。 接触疟疾的婴儿。此外，一些研究发现，患有胎盘炎的母亲所生的婴儿 疟疾降低了对儿童常规疫苗接种的反应。因此，预防胎盘 通过增强化学预防，疟疾诱导的免疫耐受有可能增加 儿童早期的纵向疟疾特异性和整体免疫力。 这个K23建议的目标是检验子宫内疟疾感染诱导耐受性的假设 胎儿疟疾特异性和全身免疫反应被增强的产前疟疾抑制 化学预防我们将通过以下方法确定子宫内疟疾暴露的免疫学后果： 以下三个目标：1）确定子宫内疟疾暴露和产前化学预防对 疟疾特异性T细胞免疫反应在儿童早期。2)为了确定子宫内疟疾的影响 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）评估子宫内疟疾暴露对常规免疫应答的影响。 预防针为了实现这些目标，我们将利用现有的基础设施和样本， 母婴对参加了一项正在进行的高效青蒿素为基础的随机临床试验， 乌干达产前疟疾化学预防。本申请中提出的研究将建立在 候选人的初步发现表明脐带血免疫调节反应的发展 在子宫内感染疟疾的婴儿中。 候选人的职业目标是破译感染性疾病的生物学基础， 贫困人口，并将这些发现应用于应对全球健康挑战。在此K23应用程序中， 候选人已经概述了一个详细的研究和职业发展计划，以配合她的职业目标。 她将获得免疫学研究先进技术的额外培训，国际合作， 研究和生物统计分析。通过对联合国系统的评估产生的数据和技术培训 提出的目标将作为一个框架，以建立一个R 01提交评价宿主-病原体相互作用的 疟疾

Project Summary/Abstract 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 proposed aims will serve as a framework to build a R01 submission evaluating host-pathogen interactions of malaria.