MICROBIAL SUCCESSION AND ADAPTIVE IMMUNE RESPONSES IN THE PREMATURE INFANT

摘要：人类婴儿在子宫内通常是不育的，然后出生在一个由微生物统治的世界， 其选择性地占据新生儿的体表和肠道。的组装 早期人类微生物组尤其是与极低出生体重（VLBW; <1500 g）婴儿相关的问题， 其中感染和免疫和炎症反应的激活产生急性发病率和莫尔- 使眼睛、肠道和中枢神经系统的共病性疾病恶化。但 改变或多或少致病微生物的初级定殖和次级持久性的选择力 在发育中的微生物群中，特别是在人类中，还没有很好的了解。具体而言， 适应性免疫应答识别哪种定植以及适应性应答如何促进 塑造早产儿的微生物组，以及微生物组如何影响并发症和并发症， 目前对适应性免疫发育的认识还很有限。拟议研究的近期目标是 识别来自早产儿肠道先锋微生物组的抗原， 自然产生的抗体和适应性体液反应。这项工作将决定是否以及如何 外周和粘膜抗体应答改变了继发性定殖的动力学。中央hypoth- 出生时存在的天然抗体改变了原发性定植，而开创性革兰氏阳性菌的抗原 阴性肠道细菌驱动适应性抗体反应， 免疫记忆这一假设将通过一种创新的分子工具组合来解决， 本研究的主要目的是：1）确定天然抗体和适应性抗体与定植的关系 2）确定母乳伊加对母乳微生物的特异性， 和早期肠道微生物组，和3）为了测量VLBW婴儿的特异性抗原， 新生儿微生物组在生命的第一年被抗体识别。这些研究将独特地定义 由早产儿和母体天然和适应性抗体识别的抗原群， 成为殖民地。通过确定粘膜抗体反应和SPE之间的动态界面， 新生儿宿主识别的特异性抗原，可以设想新的干预措施， 通过刺激天然和适应性抗体改变婴儿的原发性和继发性定植。在 这些进展可能导致改变长期结果的方法，包括传染病，过敏， 和代谢综合征。

ABSTRACT: The human infant is typically sterile in utero and then born into a world dominated by microbes, which selectively assume residence of the body surfaces and enteric tract of the newborn. The assembly of the early human microbiome is particularly an issue relevant to the very low birth weight (VLBW; <1500 g) infant, where infection and activation of immunological and inflammatory responses produce acute morbidity and mor- tality and exacerbate co-morbid diseases of the eyes, enteric tract, and central nervous system. However, the selective forces that alter primary colonization and secondary persistence of more or less pathogenic microbes within the developing microbiota are not well understood, particularly in humans. Specifically, the extent to which colonization is recognized by the adaptive immune response and how the adaptive responses contribute to shaping the microbiome of the premature infant, and how the microbiome influences concurrent and subse- quent adaptive immune development, is poorly understood. The immediate goal of the proposed research is to identify antigens from the pioneering microbiome of the intestine in the preterm infant that are recognized by natural birth antibodies and the adaptive humoral response. This work will then determine whether and how the peripheral and mucosal antibody response alters the dynamics of secondary colonization. The central hypoth- esis is that natural antibodies present at birth modify primary colonization while antigens of pioneering Gram negative enteric bacteria drive adaptive antibody responses that alter secondary colonization and long-term immune memory. The hypothesis will be addressed through an innovative combination of molecular tools in the following aims: 1) To determine the relationship between natural and adaptive antibodies and colonization of the VLBW infant intestinal tract, 2) To determine the specificity of breast milk IgA to the breast milk microbi- ome and the early intestinal microbiome in the VLBW infant, and 3) To measure the specific antigens of the neonatal microbiome recognized by antibodies in the first year of life. These studies will uniquely define the constellation of antigens recognized by preterm infant and maternal natural and adaptive antibodies as the in- fant becomes colonized. By determining the dynamic interface between mucosal antibody response and spe- cific antigens recognized by the newborn human host, new interventions may be envisioned through which to alter primary and secondary colonization of infants through stimulation of natural and adaptive antibodies. In turn these advents may lead to approaches to alter long-term outcomes including infectious diseases, allergy, and metabolic syndrome.