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

母体病毒组和 HIV 状态对婴儿肠道病毒组、生长和免疫的影响

基本信息

批准号：
10693179
负责人：
Heather Beryl Jaspan
金额：
$ 79.87万
依托单位：
SEATTLE CHILDREN'S HOSPITAL
依托单位国家：
美国
项目类别：
财政年份：
2020
资助国家：
美国
起止时间：
2020-09-21 至 2025-08-31
项目状态：
未结题

来源：
https://reporter.nih.gov/project-details/10693179
关键词：
16S ribosomal RNA sequencing Acceleration Adjuvant Adult Antibiotic Prophylaxis Antiviral Therapy Bacteria Bacteriophages Biological Assay Birth Cell Maturation Cells Clustered Regularly Interspaced Short Palindromic Repeats Communities Data Development Disease Enteral Exposure to Feces Germ-Free Growth Growth and Development function HIV HIV Infections Health Human Human Microbiome Immune Immunity Immunologics Infant Infant Health Inherited Intestines Life Linear Regressions Link Maternal Health Measures MicroRNAs Modeling Mothers Mus Natural Killer Cells Neonatal Nucleic Acids Nucleic acid sequencing Outcome Parents Phenotype Plasma Play Population Postpartum Period Probiotics Role Sampling Shapes T-Cell Development T-Lymphocyte Testing Therapeutic Time Vagina Vertical Transmission Viral Virus Work bacterial community bacteriome feeding gut inflammation gut microbiome immune activation immunological diversity immunoregulation infancy infant morbidity infant morbidity/mortality intestinal barrier maternal microbiota metagenome metagenomic sequencing microbial microbiome microbiota novel virus particle success therapy development transmission process vector vaccine virome virus identification

项目摘要

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.

项目总结/摘要生命早期的微生物组在健康和疾病中起着重要作用，包括免疫发育和成熟母体微生物群是婴儿微生物群的主要决定因素。研究调查产妇- 婴儿微生物群的传播及其对婴儿免疫力的影响集中在细菌成分然而，母体病毒组对婴儿病毒组的影响在很大程度上是未知的，早期的生活是有限的。感染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，并改变免疫力，包括免疫激活，即使他们没有感染艾滋病毒自己人们做了很多工作来了解这种现象的原因。考虑到肠道病毒组在艾滋病毒感染中扩大，我们的初步数据显示，出生时感染艾滋病毒的婴儿- 受感染的母亲比未受感染的婴儿继承的病毒种类更多。因此，与细菌类似，肠道病毒组也可以在调节免疫反应性方面发挥重要作用，婴儿的成长。我们假设婴儿肠道病毒是垂直转移的， HIV感染母亲所生婴儿的肠道病毒导致免疫个体发育加速，激活，这会影响感染艾滋病毒的婴儿的发病率。我们建议： 1：确定母体病毒组对婴儿肠道病毒组的影响，并比较病毒组的演替在出生后的前9个月内暴露于和未暴露于艾滋病毒的婴儿中。匹配母亲的病毒组- 婴儿对将通过从纯化的病毒颗粒分离的核酸的宏基因组测序来确定。母体粪便和阴道病毒组组成将与婴儿第一周的肠道病毒组组成相关产后肠道病毒组的组成将比较婴儿之间的接触和未接触在出生后的第一周、第4周、第15周和第36周感染艾滋病毒。 2：评估婴儿粪便中病毒组和细菌微生物群之间的关系。我们将评估噬菌体与其细菌靶标的纵向关系。 3、探讨婴幼儿肠道病毒组与肠道炎症、免疫个体发生的关系线性增长。为了验证暴露于以下物质的未感染婴儿中的肠道病毒组扩展的假设， HIV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NK和T细胞在生命的前9个月使用CyTOF分析个体发育。为了测试病毒组是否会改变免疫个体发育，我们将喂养婴儿小鼠与细菌宿主和无细菌宿主，并评估对免疫力的影响。了解塑造婴儿肠道病毒组的因素及其对细菌微生物群的影响，免疫个体发育和线性生长可以促进干预措施的发展，以降低婴儿发病率和死亡率，特别是那些接触艾滋病毒的人。