The Immunologic Impact of In Utero Malaria Exposure and Prenatal Chemoprevention

子宫内疟疾暴露和产前化学预防的免疫影响

• 批准号: 10379695
• 负责人: Mary Prahl
• 金额: $ 5.4万
• 依托单位: UNIVERSITY OF CALIFORNIA, SAN FRANCISCO
• 依托单位国家: 美国
• 财政年份: 2017
• 资助国家: 美国
• 起止时间: 2017-07-01 至 2023-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10379695
• 关键词: Address; Affect; Anemia; Antigens; Area; Artemisinins; Biological; Biometry; Birth; Chemoprevention; Child; Childhood; Communicable Diseases; Data; Development; Development Plans; Enrollment; Evaluation; Fetal Growth Retardation; Goals; Immune Tolerance; Immune response; Immunity; Immunologics; Immunology; Infant; Infrastructure; Innate Immune Response; International; Life; Low Birth Weight Infant; Malaria; Malaria Vaccines; Mothers; Phenotype; Poverty; Pregnancy; Prevention; Public Health; Randomized Clinical Trials; Reporting; Research; Risk; Sampling; T-Lymphocyte; Techniques; Testing; Training; Uganda; Umbilical Cord Blood; Vaccination; Woman; adaptive immune response; adverse birth outcomes; base; career; career development; cohort; early childhood; fetal; global health; immunogenicity; immunoregulation; improved; in utero; malaria infection; parent grant; pathogen; placental malaria; prenatal; research and development; response; stillbirth; vaccination strategy; vaccine response

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.

项目摘要/摘要自家长资助以来未发生变化 据估计，怀孕期间的疟疾影响了超过 1200 万妇女，导致许多人 不良分娩结局，包括低出生体重、死产、产妇贫血和宫内生长 限制。目前唯一可用的疟疾疫苗因儿童免疫原性差而受到限制 生活在疟疾流行地区。据报道，患有胎盘疟疾的母亲所生的孩子 生命最初几年患疟疾的风险增加。最近的研究揭示了胎儿的有趣证据 对疟疾抗原的耐受性，表明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在子宫内疟疾中得到证实 接触。胎盘脐带血中已描述了一种耐受性或免疫调节性 T 细胞表型 暴露于疟疾的婴儿。此外，一些研究发现，有胎盘的母亲所生的婴儿 疟疾降低了对常规儿童疫苗接种的反应。因此，预防胎盘 通过加强化学预防，疟疾诱导的免疫耐受有可能增强 幼儿期的纵向疟疾特异性和整体免疫力。 K23 提案的目标是检验子宫内疟疾感染诱发耐受性的假设 胎儿疟疾特异性和整体免疫反应受到产前疟疾增强的抑制 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 儿童早期疟疾特异性 T 细胞免疫反应。 2) 确定子宫内疟疾的影响 早期疟疾感染期间暴露和产前化学预防对先天免疫反应的影响 3) 评估子宫内疟疾暴露对常规免疫反应的影响 疫苗接种。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的样本 母婴对参加了一项正在进行的基于高效青蒿素的随机临床试验 乌干达的产前疟疾化学预防。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 在子宫内暴露于疟疾的婴儿中。 候选人的职业目标是破译困扰人类的传染病的生物学基础 贫困人口，并应用这些发现来应对全球健康挑战。在此 K23 应用程序中， 候选人已概述了适合其职业目标的详细研究和职业发展计划。 她将获得免疫学研究先进技术、国际合作等方面的额外培训 研究和生物统计分析。通过目标评估产生的数据和技术培训 将作为构建评估疟疾宿主与病原体相互作用的 R01 提交的框架。

项目成果

Minimal mRNA uptake and inflammatory response to COVID-19 mRNA vaccine exposure in human placental explants.

人类胎盘外植体中对 COVID-19 mRNA 疫苗暴露的最小 mRNA 摄取和炎症反应。

• DOI: 10.1101/2023.02.01.23285349
• 发表时间: 2023
• 期刊: medRxiv : the preprint server for health sciences
• 作者: Gonzalez,Veronica;Li,Lin;Buarpung,Sirirak;Prahl,Mary;Robinson,JoshuaF;Gaw,StephanieL
• 通讯作者: Gaw,StephanieL