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

• 批准号: 10267757
• 负责人: Heather Beryl Jaspan
• 金额: $ 74.56万
• 依托单位: SEATTLE CHILDREN'S HOSPITAL
• 依托单位国家: 美国
• 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/10267757
• 关键词: 16S ribosomal RNA sequencing; 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 Disease Transmission; Viral; Virus; Work; bacterial community; bacteriome; base; feeding; gut microbiome; immune activation; immunological diversity; infancy; infant morbidity; infant morbidity/mortality; inflammatory disease of the intestine; intestinal barrier; maternal microbiota; metagenome; metagenomic sequencing; microbial; microbiome; microbiota; novel virus; particle; therapy development; transmission process; vector vaccine; virome

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.

项目概要/摘要 生命早期微生物组在健康和疾病中发挥着重要作用，包括免疫发育和 成熟。母体微生物群是婴儿微生物群的主要决定因素。研究调查母亲- 婴儿微生物群的传播及其对婴儿免疫力的影响主要集中在细菌上 成分。然而，母体病毒组对婴儿病毒组的影响在很大程度上尚不清楚，并且对病毒组的研究 在生命早期是有限的。感染艾滋病毒的母亲所生的婴儿更容易患病、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。为了理解这种现象的原因，人们进行了大量的工作。鉴于肠溶 病毒组在艾滋病毒感染中扩大，因此我们的初步数据显示感染艾滋病毒的婴儿并不奇怪 受感染的母亲比未接触病毒的婴儿继承了更广泛的病毒。因此，与细菌类似 微生物组、肠道病毒组也可以在调节免疫反应和 婴儿的成长。我们假设婴儿肠道病毒组是垂直转移的，并且扩展的 感染艾滋病毒的母亲所生婴儿的肠道病毒组会导致免疫个体发育加速， 激活，这会影响暴露于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演替 出生后 9 个月内接触和未接触 HIV 的婴儿。匹配的母亲的病毒组 婴儿对将通过从纯化的病毒颗粒中分离的核酸的宏基因组测序来确定。 母亲粪便和阴道病毒组的组成将与第一周婴儿肠道的病毒组组成相关 产后。将比较暴露和未暴露的婴儿的肠道病毒组的组成 在生命的第一周、第 4 周、第 15 周和第 36 周感染 HIV。 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之间的纵向关系。 3：评估婴儿肠道病毒组与肠道炎症、免疫个体发育的关系 和线性增长。检验以下假设：未受感染的婴儿暴露于 HIV 有助于生命早期更大的免疫多样性，我们将纵向评估循环 NK 和 T 细胞 在生命的前 9 个月内使用 CyTOF 分析进行个体发育。测试病毒组是否导致改变 免疫个体发育，我们将用带有或不带有细菌宿主的噬菌体喂养幼年小鼠，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，特别是对于那些接触艾滋病毒的人来说。