Identifying inter-kingdom microbial determinants of altered immunity in HIV exposed infants

确定 HIV 暴露婴儿免疫力改变的跨界微生物决定因素

• 批准号: 10326871
• 负责人: Bryan P Brown
• 金额: $ 13.17万
• 依托单位: SEATTLE CHILDREN'S HOSPITAL
• 依托单位国家: 美国
• 财政年份: 2021
• 资助国家: 美国
• 起止时间: 2021-09-01 至 2023-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10326871
• 关键词: 16S ribosomal RNA sequencing; Adult; Animals; BCG Live; BCG Vaccine; Bacille Calmette-Guerin vaccination; Bacteria; Bacterial Vaccines; Bacteriophages; Bayesian Analysis; Biological Assay; Cells; Colon; Communities; Data; Data Set; Development; Disease; Disease susceptibility; Enteral; Etiology; Feces; Funding; Gene Expression; Germ-Free; Gnotobiotic; HIV; HIV Infections; Health; Human; Human Microbiome; Immune; Immune response; Immunity; Immunization; Immunize; Infant; Intestines; Life; Linear Regressions; Link; Mediating; Metagenomics; Microbe; Modeling; Morbidity - disease rate; Mothers; Mucosal Immunity; Mucous Membrane; Neonatal; Peripheral; Play; Probiotics; Research; Role; Shapes; Shotguns; Spleen; Statistical Data Interpretation; T cell response; T-Lymphocyte; T-Lymphocyte Subsets; Techniques; Testing; Therapeutic; Vaccination; Vaccines; Viral; Virion; Virus; Whole Blood; Work; adaptive immunity; bacterial community; bacteriome; base; cohort; cytokine; experimental group; experimental study; gut bacteria; gut dysbiosis; gut microbiome; gut microbiota; high risk; insight; metagenome; microbial; microbiome; microbiota; mouse model; multiple omics; pup; response; single-cell RNA sequencing; vaccine response; virome

PROJECT ABSTRACT Infants born to HIV-infected mothers are at high risk for HIV acquisition. Additionally, HIV-exposed yet uninfected infants display reduced vaccine responses and increased disease susceptibility compared to unexposed infants. The development of certain T cell subsets, both in the mucosa and systemically, is determined by the presence of specific microbes in the gut and may be important in determining adaptive immunity. However, the gut microbiota of HIV-exposed uninfected (iHEU) infants differs from that of HIV- unexposed (iHU) infants, since their mothers have altered gut microbiota. The gut virome also plays a central role in modulating both the bacterial microbiota and immune response of adults, yet the association between the infant enteric virome and cellular responses to vaccination has not yet been explored. This study proposes that the enteric virome is one of the factors influencing the morbidity of HIV-exposed infants, either by directly altering mucosal immunity or by altering the composition of enteric bacterial communities, as a consequence of bacteriophage or other viral dynamics. This proposal will utilize an already funded, ongoing cohort to longitudinally identify interactions between viruses, bacterial microbiota, and cellular responses to vaccination in 40 iHEU and 40 iHU (Aim 1). Viral metagenome data will be integrated with bacterial community datasets and T cell cytokine responses to BCG vaccination to identify viral and bacterial taxa correlated with BCG responses. The effect of the expanded virome on bacterial microbiota and responses to BCG vaccination will then be assessed for causality in gnotobiotic mouse models (Aim 2). The effect of the expanded iHEU viroem on mucosa and peripheral gene expression will be assayed using single cell RNA sequencing in Aim 3. Integrative analyses will be used to identify interactions between specific bacterial and viral taxa, as well as their associated with BCG responses. Together, these Aims will identify mechanisms of gut dysbiosis in iHEU and reveal potential therapeutics to restore health to this group. Collectively, this proposal will reveal how maternal HIV infection shapes the enteric microbiome and immunity of associated infants.

项目摘要 感染艾滋病毒的母亲所生的婴儿感染艾滋病毒的风险很高。此外，感染艾滋病毒的人还没有 与未感染的婴儿相比，未感染的婴儿表现出疫苗反应减少和疾病易感性增加 未接触过的婴儿。某些T细胞亚群的发育，无论是在粘膜中还是在系统中，都是 由肠道中特定微生物的存在决定，在确定适应能力方面可能很重要 豁免权。然而，未感染艾滋病毒的婴儿(IHEU)的肠道微生物区系不同于艾滋病毒感染的婴儿。 未暴露(IHU)婴儿，因为他们的母亲改变了肠道微生物区系。肠道病毒也扮演着一个中心角色 在调节细菌微生物区系和成人免疫反应方面的作用，但两者之间的联系 婴儿肠道病毒群和细胞对接种疫苗的反应尚未被探索。这项研究提出 肠道病毒是影响感染艾滋病毒婴儿发病率的因素之一，无论是通过直接还是通过 改变粘膜免疫或通过改变肠道细菌群落的组成，作为以下结果 噬菌体或其他病毒动力学。这项提案将利用已经获得资金的持续队列来 纵向确定病毒、细菌微生物区系和细胞对接种疫苗的反应之间的相互作用 在40个IHEU和40个IHU(目标1)中。病毒元基因组数据将与细菌群落数据集整合 和T细胞细胞因子对卡介苗接种的反应，以确定与卡介苗相关的病毒和细菌分类群 回应。扩大病毒体对细菌微生物区系的影响及对卡介苗接种的反应 然后在灵知生菌小鼠模型中评估因果关系(目标2)。扩大的IHEU病毒株的效果 在AIM 3中，将使用单细胞RNA测序来分析粘膜和外周基因的表达。 综合分析将用于确定特定细菌和病毒分类群之间的相互作用，以及 它们与卡介苗的反应有关。总之，这些目标将确定IHEU肠道生物失调的机制。 并揭示了恢复这一群体健康的潜在疗法。总而言之，这项提案将揭示 母体感染艾滋病毒塑造了相关婴儿的肠道微生物群和免疫力。