Influence of maternal virome and HIV status on infant gut virome, growth and immunity

项目摘要/摘要 早期生命微生物群在健康和疾病中发挥着重要作用，包括免疫发育和 成熟。母体微生物区系是婴儿微生物区系的主要决定因素。调查母亲的研究- 婴儿微生物区系的传播及其对婴儿免疫的影响主要集中在细菌 组件。然而，母体病毒对婴儿病毒的影响在很大程度上是未知的，对病毒的研究 在早期生命中是有限的。携带艾滋病毒的母亲所生的婴儿更容易感染疾病，发育迟缓 生长，并改变了免疫力，包括免疫激活，即使他们没有感染艾滋病毒 他们自己。为了理解这一现象的原因，人们做了大量的工作。考虑到肠道 病毒在艾滋病毒感染中扩大，因此我们的初步数据显示，艾滋病毒所生婴儿- 受感染的母亲比未接触病毒的婴儿遗传的病毒范围更广。因此，类似于细菌 肠道病毒体也可以在调节免疫反应性和 婴儿的生长发育。我们假设婴儿肠道病毒是垂直传播的，并且扩展的 感染艾滋病毒的母亲所生婴儿的肠道病毒可以加速免疫个体发育和 活跃性，这会影响接触艾滋病毒婴儿的发病率。我们建议： 1.测定母体病毒对婴儿肠道病毒的影响，并比较病毒的演替 在生命的头9个月期间暴露于艾滋病毒的婴儿和未暴露于艾滋病毒的婴儿。配对母亲的病毒- 婴儿配对将通过对从纯化的病毒颗粒中提取的核酸进行元基因组测序来确定。 母体粪便和阴道病毒的组成将在第一周与婴儿肠道的组成相关 产后。肠道病毒群的组成将在暴露和未暴露的婴儿之间进行比较。 在生命的第一周、4周、15周和36周内感染艾滋病毒。 2：探讨婴幼儿粪便中病毒体与细菌菌群的关系。我们将评估 噬菌体与其细菌靶标的纵向关系。 3：评估婴幼儿肠道病毒群与肠道炎症、免疫个体发育的关系 和线性增长。为了验证这样一种假设，即在未感染的婴儿中暴露于 艾滋病毒在生命早期有助于更大的免疫多样性，我们将纵向评估循环中的NK和T细胞 在生命的前9个月使用细胞周期分析进行个体发育。测试病毒是否会引起改变 免疫个体发育，我们将用带有和不带有细菌宿主的噬菌体喂养幼鼠，并评估 对免疫力的影响。 了解形成婴儿肠道病毒群的因素及其对细菌微生物区系的影响， 免疫个体发育和线性生长可以促进干预措施的发展，以减少婴儿发病率 和死亡率，特别是对那些接触艾滋病毒的人来说。

PROJECT SUMMARY/ABSTRACT The early life microbiome plays a significant role in health and disease, including immune development and maturation. Maternal microbiota is a major determinant of infant microbiota. Studies investigating maternal- infant microbiota transmission and its consequent influence on infant immunity have focused on the bacterial component. Yet the impact of maternal virome on infant virome is largely unknown, and studies of the virome in early life are limited. Infants born to mothers living with HIV are more vulnerable to diseases, have stunted growth, and have altered immunity, including immune activation, even when they are not infected with HIV themselves. Much work has gone into understanding the reasons for this phenomenon. Given that the enteric virome is expanded in HIV infection, it is not surprising that our preliminary data show that infants born to HIV- infected mothers inherit a wider range of viruses than unexposed infants. Thus, similarly to the bacterial microbiome, the gut virome could also play an important role in modulating immune responsiveness and growth of infants. We hypothesize that the infant enteric virome is vertically transferred, and the expanded enteric virome of infants born to mothers who are HIV-infected leads to accelerated immune ontogeny and activation, which influences the morbidity of infants exposed to HIV. We propose to: 1: Determine the influence of maternal virome on the infant enteric virome and compare the virome succession in infants exposed and unexposed to HIV through the first 9 months of life. The viromes of matched mother- infant pairs will be determined via metagenomic sequencing of nucleic acid isolated from purified viral particles. Maternal fecal and vaginal virome composition will be correlated with that of the infants’ gut in the first week postpartum. The composition of the enteric virome will be compared between infants exposed and unexposed to HIV during the first week, 4, 15 and 36 weeks of life. 2: Evaluate the relationship between the virome and the bacterial microbiota in infant stool. We will assess the relationship between bacteriophage and their bacterial targets longitudinally. 3: Evaluate the relationship between the infant enteric virome and intestinal inflammation, immune ontogeny and linear growth. To test the hypothesis that the expanded enteric virome in uninfected infants exposed to HIV contributes to greater immune diversity in early life, we will longitudinally assess circulating NK and T cell ontogeny using CyTOF analysis over the first 9 months of life. To test whether the virome causes altered immune ontogeny, we will feed infant mice with phages with and without their bacterial hosts and evaluate the effect on immunity. Understanding the factors that shape the infant gut virome and its consequent impact on bacterial microbiota, immune ontogeny and linear growth could facilitate the development of interventions to reduce infant morbidity and mortality, particularly for those who are exposed to HIV.