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.

项目摘要/摘要早期生命微生物组在健康和疾病中起着重要作用，包括免疫发展和成熟。孕产妇微生物群是婴儿菌群的主要决定。研究成熟的研究婴儿菌群传播及其对婴儿免疫的影响已集中在细菌上成分。然而，母体病毒蛋白对婴儿病毒蛋白的影响在很大程度上尚不清楚，并且对病毒素的研究在早期生活有限。患有艾滋病毒母亲的母亲出生的婴儿更容易受到疾病的影响生长并改变了免疫学，包括免疫激活，即使未感染HIV 自己。理解这种现象的原因已经进行了很多工作。鉴于输入 Virome在艾滋病毒感染中扩大了，我们的初步数据表明，艾滋病毒出生的婴儿毫不奇怪被感染的母亲继承了比意外婴儿更广泛的病毒。那类似于细菌微生物组，肠道病毒瘤也可以在调节免疫反应性和婴儿的生长。我们假设婴儿启动子病毒素是垂直转移的，并且扩展了受HIV感染的母亲出生的婴儿的肠病毒蛋白酶导致免疫本体发育和激活会影响暴露于HIV的婴儿的发病率。我们建议： 1：确定母体病毒蛋白对婴儿肠道病毒蛋白的影响并比较病毒蛋白的成功在婴儿生命的前9个月中暴露于艾滋病毒的婴儿中。匹配的母亲的病毒瘤 - 婴儿对将通过从纯化的病毒颗粒中分离出的核酸的核酸测序来确定。孕产妇粪便和阴道病毒蛋白的成分将与婴儿在第一周的肠道相关产后。在暴露于婴儿和意外的婴儿之间，将比较肠道病毒蛋白的组成在第一周，4、15和36周的第一周向艾滋病毒。 2：评估婴儿粪便中病毒蛋白与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之间的关系纵向。 3：评估婴儿肠道病毒蛋白与肠道感染，免疫个体发育之间的关系和线性增长。为了检验以下假设：暴露于未感染的婴儿中扩张的启动子病毒蛋白艾滋病毒在早期生活中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个月中使用CytoF分析的个体发育。测试病毒瘤是否导致改变免疫个体发育，我们将以有或没有细菌宿主的噬菌体喂养婴儿小鼠，并评估对免疫的影响。了解塑造婴儿肠道病毒素的因素及其对细菌菌群的影响，免疫个体发育和线性生长可以支持降低婴儿发病率的干预措施的发展和死亡率，特别是对于那些接触艾滋病毒的人。