The Effect of Maternal Cells on Infant Immunity

修改项目摘要/摘要部分 尽管过去20年来全球儿童死亡率大幅下降，但2015年仍有590万儿童在五岁生日前死亡。前五大死因中有三个是感染性的，包括肺炎、腹泻和新生儿败血症。虽然外在因素，如疫苗接种，获得清洁的水，抗生素和准确的诊断是目前的公共卫生运动的目标，很少有人知道的主机内在因素，影响这些疾病的易感性。特别是，迄今为止被忽视的是少量母体细胞和胎儿在怀孕期间获得的DNA在婴儿感染中的作用，称为母体微嵌合体。该提案特别旨在了解这些母体细胞在塑造胎儿和婴儿免疫反应以及随后在儿童期免受传染病影响方面的作用。我们最近发现，分娩时有母体微嵌合体的儿童更容易感染疟疾，但与没有母体微嵌合体的儿童相比，感染后患病或住院的可能性更小。这一发现可能意味着一种自然的“疫苗接种”机制，即儿童经历感染但免受疾病的影响。我们假设这种效应是母体调节促炎性胎儿和婴儿免疫应答的结果，限制免疫介导的病理，并且这种调节可能延伸到针对全球健康重要性的其他感染的免疫应答。使用来自美国妊娠后代以及来自马里的疟疾暴露妊娠的样本和数据，我们建议确定决定获得母体微嵌合体的因素，母体细胞调节胎儿和婴儿免疫表型的能力，以及母体细胞在保护儿童免受常见感染（包括肺炎和腹泻）中的作用。我们预计，这项研究将表明，获得性母体细胞影响胎儿和婴儿的免疫反应，这将有广泛的影响围产期和出生后的感染和免疫反应。此外，证明母体细胞提供对儿童感染的保护将表明维持这种移植物的进化益处，强调代际免疫相互作用的重要性。最后，确定预测母体微嵌合体的因素可能会导致未来的目标，有意调制母体细胞作为一种新的方法，以防止免疫介导的发病率和死亡率与儿童感染的全球健康的重要性。

Modified Project Summary/Abstract Section Despite large improvements in global childhood mortality in the last 20 years, an astonishing 5.9 million children died before their fifth birthday in 2015. Three of the top five causes of death are infectious, including pneumonia, diarrhea, and neonatal sepsis. Although extrinsic factors such as vaccination, access to clean water, antibiotics, and accurate diagnostics are targets of current public health campaigns, little is known about the host intrinsic factors that affect susceptibility to these illnesses. In particular, thus far overlooked is the role of a small number of maternal cells and DNA acquired by the fetus during pregnancy, known as maternal microchimerism, in infant infection. This proposal specifically seeks to understand the role of these maternal cells in shaping fetal and infant immune responses and subsequent protection from infectious diseases during childhood. We recently found that children with maternal microchimerism at delivery were more likely to become infected with malaria but, when infected, were less likely to become sick or to be hospitalized as compared to children without maternal microchimerism. This finding may imply a mechanism of natural “vaccination” whereby children experience infection but are protected from disease. We hypothesize that this effect is the result of maternal regulation of pro-inflammatory fetal and infant immune responses, limiting immune-mediated pathology, and that such regulation may extend to immune responses directed against other infections of global health importance. Using samples and data from offspring of US pregnancies as well as malaria-exposed pregnancies from Mali, we propose to identify the factors that determine the acquisition of maternal microchimerism, the ability of maternal cells to modulate the immune phenotype of the fetus and infant, and the role of maternal cells in protection from common childhood infections, including pneumonia and diarrhea. We anticipate that this study will demonstrate that acquired maternal cells influence fetal and infant immune responses, which would have broad implications for perinatal and postnatal infections and response to immunization. In addition, demonstrating that maternal cells provide protection against childhood infections would suggest an evolutionary benefit to maintaining this graft, emphasizing the importance of intergenerational immune interactions. Finally, identification of the factors that predict maternal microchimerism may lead to future targets for intentional modulation of maternal cells as a novel approach to prevent the immune-mediated morbidity and mortality associated with childhood infections of global health importance.