The effect of malaria during pregnancy on infant susceptibility to malaria

妊娠期疟疾对婴儿疟疾易感性的影响

基本信息

批准号：
9121347
负责人：
SARAH BOUDOVA
金额：
$ 3.74万
依托单位：
UNIVERSITY OF MARYLAND BALTIMORE
依托单位国家：
美国
项目类别：
财政年份：
2014
资助国家：
美国
起止时间：
2014-09-01 至 2017-08-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/9121347
关键词：
Accounting Affect Anemia Anti-Inflammatory Agents Anti-inflammatory Antigens Biological Assay Birth Blood Circulation Cells Child Chloroquine Chronic Clinical Clinical Trials Ear Effector Cell Environmental Exposure Etiology Exposure to Fetus Fingers Flow Cytometry Frequencies Goals Health Immune Immune Tolerance Immune response Immune system Immunity Immunosuppressive Agents Incidence Infant Infant Health Infant Mortality Infection Infection prevention Inflammation Inflammatory Intervention Left Life Low Birth Weight Infant Malaria Malaria prevention Malawi Maternal Exposure Molecular Morbidity - disease rate Mothers Neonatal Newborn Infant Observational Study Peripheral Personal Satisfaction Pharmaceutical Preparations Phenotype Placenta Play Policy Maker Positioning Attribute Predisposition Pregnancy Pregnant Women Premature Birth Prevalence Prevention strategy Production Prophylactic treatment Pyrimethamine-Sulfadoxine Randomized Randomized Clinical Trials Randomized Controlled Clinical Trials Regulatory T-Lymphocyte Research Personnel Risk Role Serum Staging T-Lymphocyte Time Training Treatment Protocols Umbilical Cord Blood Weight Gain Woman arm cytokine design fetal fighting infancy malaria infection mortality neonatal immune system neonatal immunity novel peripheral blood placental malaria pregnant prevent public health intervention public health relevance response theories

项目摘要

DESCRIPTION (provided by applicant): Malaria during pregnancy threatens the health of the mother and newborn. It causes maternal anemia, low birth weight, and infant mortality. In addition, pregnancy-associated malaria has long-lasting consequences on infant health that may be attributable to the effect of maternal malaria on the fetal immune system. Children born to mothers with placental malaria have increased risk of malaria in infancy. However, because these results are from observational studies, it cannot be determined if placental malaria alters susceptibility to malaria or whether infants born to women exposed to a heavy burden of malaria while pregnant will also be exposed to more malaria after birth. Another shortcoming of these studies is limiting the assessment of malaria during pregnancy to examination of the placenta at delivery. Peripheral malaria in pregnancy may also alter the infants' susceptibility to infection. The proposed mechanism for the effect of pregnancy-associated malaria on infant malaria susceptibility is malaria antigens crossing through the placenta into fetal circulation. This cause priming of the immune system and the induction of either immune tolerance or sensitization, with increased or decreased risk of malaria in infancy, respectively. However it is unknown what drives the infant's immune system towards tolerance versus sensitization. We hypothesize that chronic exposure to malaria antigens from placental malaria induces tolerance while transient exposure from maternal peripheral malaria induces sensitization. We have a unique opportunity to examine the effect of peripheral and placental malaria on infant risk of malaria through a clinical trial that will randomly apply interventions to alter fetal malaria exposure. In 2012, we began a randomized clinical trial of continuous prophylaxis versus intermittent treatment for malaria in pregnancy which will yield three distinct malaria exposure groups: (1) placental malaria; (2) peripheral malaria without placental infection; and (3) no malaria during pregnancy. In this proposed study, we will follow infants born to mothers in the clinical trial for the first ear of life conducting active and passive surveillance for malaria. In Aim 1 we hypothesize that children born to mothers with placental malaria will have the highest incidence of malaria in infancy, while children born to mothers with peripheral malaria will have the lowest incidence. In Aim 2 we hypothesize that children born to mothers with placental malaria will have a tolerogenic immune phenotype characterized by elevated T regulatory cells (Tregs), and immunosuppressive cytokines, while children born to mothers with peripheral malaria will have a sensitized immune phenotype characterized by elevated T effector cells and production of pro-inflammatory cytokines. We will use 12-parameter flow cytometry to rigorously identify Tregs from cord blood and cytometric bead array assays to determine the levels of cytokines in neonatal serum. We will determine the effect of maternal malaria on fetal immunity and infant susceptibility to malaria. With this new information, researchers and policy makers will be able to design new strategies to protect both pregnant women and newborns throughout the malaria-endemic world.

描述（由申请人提供）：怀孕期间的疟疾威胁到母亲和新生儿的健康。它会导致母亲贫血，低出生体重和婴儿死亡率。此外，与妊娠相关的疟疾对婴儿健康产生了长期的后果，这可能归因于产妇疟疾对胎儿免疫系统的影响。患有胎盘疟疾的母亲出生的孩子在婴儿期患疟疾的风险增加。但是，由于这些结果来自观察性研究，因此无法确定胎盘疟疾是否改变了对疟疾的易感性，或者是否在怀孕期间承受着沉重的疟疾负担的妇女出生的婴儿是否也会在出生后会暴露于更多的疟疾。这些研究的另一个缺点是将怀孕期间的疟疾评估限制为在分娩时检查胎盘。怀孕期间疟疾也可能改变婴儿对感染的敏感性。提出的与妊娠相关疟疾作用对婴儿疟疾易感性作用的机制是疟疾抗原穿过胎盘中的疟疾抗原进入胎儿循环。这种原因的免疫系统启动以及免疫耐受性或敏化的诱导分别增加或降低了婴儿期疟疾的风险。然而，尚不清楚是什么驱动婴儿的免疫系统朝着耐受性而敏感的阳性。我们假设长期暴露于胎盘疟疾中的疟疾抗原会诱导耐受性，而孕产妇周围疟疾的短暂暴露会诱导敏感性。我们有一个独特的机会，可以通过一项临床试验来检查外周和胎盘疟疾对疟疾风险的影响，该试验将随机采用干预措施来改变胎儿疟疾的暴露。 2012年，我们开始了一项随机临床试验，该试验是对怀孕期间疟疾的连续预防与间歇性治疗，这将产生三个不同的疟疾暴露组：（1）胎盘疟疾；（2）没有胎盘感染的外周疟疾；（3）怀孕期间没有疟疾。在这项拟议的研究中，我们将跟随母亲在临床试验中为母亲出生的婴儿，以进行疟疾的主动和被动监测的第一次生命耳朵。在AIM 1中，我们假设患有胎盘疟疾的母亲所生的孩子在婴儿期的发病率最高，而周围疟疾的母亲出生的孩子的发生率最低。 In Aim 2 we hypothesize that children born to mothers with placental malaria will have a tolerogenic immune phenotype characterized by elevated T regulatory cells (Tregs), and immunosuppressive cytokines, while children born to mothers with peripheral malaria will have a sensitized immune phenotype characterized by elevated T effector cells and production of pro-inflammatory cytokines.我们将使用12参数流式细胞术来严格识别脐带血和细胞仪阵列分析的Treg，以确定新生儿血清中细胞因子的水平。我们将确定孕产妇疟疾对胎儿免疫和婴儿对疟疾的敏感性的影响。有了这些新信息，研究人员和政策制定者将能够设计新的策略，以保护整个疟疾流行世界的孕妇和新生儿。