Identifying inter-kingdom microbial determinants of altered immunity in HIV exposed 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，艾滋病毒感染者尚未 未受感染的婴儿与未受感染的婴儿相比， 未暴露的婴儿某些T细胞亚群的发展，无论是在粘膜和全身， 由肠道中特定微生物的存在决定，并且可能在确定适应性方面很重要。 免疫力然而，暴露于艾滋病毒的未感染婴儿（iHEU）的肠道微生物群与艾滋病毒感染婴儿的肠道微生物群不同。 未暴露（iHU）的婴儿，因为他们的母亲改变了肠道微生物群。肠道病毒组也起着中心作用， 在调节细菌微生物群和成人免疫反应中的作用，但 婴儿肠道病毒组和细胞对疫苗接种的反应尚未被探索。本研究提出 肠道病毒组是影响HIV暴露婴儿发病率的因素之一， 改变粘膜免疫力或通过改变肠道细菌群落的组成， 噬菌体或其他病毒动力学。该提案将利用一个已获资助的、正在进行的队列， 纵向识别病毒、细菌微生物群和细胞对疫苗接种的反应之间的相互作用 40个iHEU和40个iHU（目标1）。病毒宏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BCG疫苗接种的反应，以鉴定与BCG相关的病毒和细菌分类群 应答扩增的病毒组对细菌微生物群的影响和对BCG疫苗接种的反应将 然后在无菌小鼠模型中评估因果关系（目的2）。扩增的iHEU病毒的作用 将使用Aim 3中的单细胞RNA测序来测定对粘膜和外周基因表达的影响。 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 与BCG反应有关。这些目标将共同确定iHEU中肠道生态失调的机制 并揭示潜在的治疗方法来恢复这一群体的健康。总的来说，这项提案将揭示如何 母亲的HIV感染影响了相关婴儿的肠道微生物组和免疫力。

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.