Microbiome-driven immune changes and growth stunting in HIV-exposed uninfected children

项目摘要 尽管怀孕期间获得抗逆转录病毒疗法的机会增加，但每年出生的超过100万儿童中， 感染艾滋病毒的孕妇（PPHIV）暴露于艾滋病毒但未感染（HEU）， 与未接触艾滋病毒的儿童相比，虽然不良高浓缩铀儿童的起源 健康结果知之甚少，越来越多的证据表明，异常的微生物组发育 可能发挥关键作用。然而，机制仍然难以捉摸，更好的机制理解是 改善护理至关重要。我们的首要目标是确定临床，环境，饮食和流行病学 与高浓缩铀儿童生长发育迟缓有关的特征， 交流，并将肠道微生物组概况与生长发育迟缓的高浓缩铀儿童的免疫发育联系起来， 多组学方法。为此，我们将利用数据、生物库和新收集的样本， 乌干达正在进行的前瞻性纵向出生队列研究，将生长发育迟缓、疟疾疾病负担和 微生物组驱动的高浓缩铀儿童免疫力变化的不利临床结果。创新：我们的疾病模型 检查和表征转移的母体免疫力、儿童肠道微生物组和 免疫概况发展和儿童生长发育迟缓是新颖的，高度相关的，概念上的创新。 我们提出的研究的明显优势包括：1）同时比较艾滋病毒暴露的样本， 和-未暴露组，以尽量减少混杂因素，2）丰富的临床、流行病学和环境暴露 充分表征的纵向组群中的数据，3）利用宏基因组学的综合多组学方法， 代谢组学和免疫组学，以确定生长发育迟缓和免疫发育的新机制。 研究人员：我们的跨学科团队，在流行病学，出生队列和传染病方面具有专业知识 （Bebell）;免疫学（Alter，Bernshtein），多组学（Mehta，Chan，Huttenhower）已经准备好完成这一任务 工作方法：我们将利用生物库样本，并延长对入组的母子二人组的随访， 博士Bebell（K23 AI 138856）出生队列，伯恩斯坦博士对系统血清学平台进行的肠溶 Mehta博士建立的多组学实验室和数据管道基础设施， 母亲艾滋病毒暴露和微生物组组成对儿童生长和免疫发育的影响， 1）确定与高浓缩铀中生长发育迟缓相关的临床元数据特征 2）描述与高浓缩铀生长发育迟缓相关的肠道微生物组特征 使用代谢组学建立宿主-微生物通讯机制; 3） 特异于病原性和非病原性的经胎盘抗体转移和母乳抗体组合物 PPHIV和生长发育迟缓的高浓缩铀儿童的肠道微生物。识别HIV相关的微生物组异常， 生长迟缓的免疫机制具有很大的潜力，可以通过告知 疫苗策略、微生物组治疗和对生长不良高危儿童的早期干预。

PROJECT SUMMARY Despite increasing access to antiretroviral therapy (ART) in pregnancy, the >1 million children born annually to pregnant people with HIV (PPHIV) who are HIV-exposed but uninfected (HEU) remain at >2-fold higher risk of growth stunting and infectious morbidity than HIV-unexposed children. Though the origins of adverse HEU child health outcomes are poorly understood, mounting evidence suggests that abnormal microbiome development may play a key role. However, the mechanisms remain elusive, and a better mechanistic understanding is essential to improve care. Our overarching goals are to identify clinical, environmental, diet, and epidemiologic features associated with growth stunting in HEU children, characterize mechanisms of host-microbe communication, and link gut microbiome profiles to immune development in growth stunted HEU children using a multi’omics approach. To do so, we will leverage data, biobanked, and newly collected samples from an ongoing prospective longitudinal birth cohort in Uganda to relate growth stunting, diarrheal disease burden, and adverse clinical outcomes to microbiome-driven changes in HEU child immunity. Innovation: Our disease model examining and characterizing relationships between transferred maternal immunity, child gut microbiome and immune profile development, and childhood growth stunting is novel, highly relevant, and conceptually innovative. Distinct advantages of our proposed research include 1) simultaneous comparison of samples from HIV-exposed and -unexposed groups to minimize confounding, 2) rich clinical, epidemiologic, and environmental exposure data in a well-characterized longitudinal cohort, 3) integrated multi’omics approach leveraging metagenomics, metabolomics, and immun’omics, to identify novel mechanisms of growth stunting and immune development. Investigators: Our interdisciplinary team with expertise in epidemiology, birth cohorts and infectious diseases (Bebell); immunology (Alter, Bernshtein), multi’omics (Mehta, Chan, Huttenhower) is well-poised to complete this work. Approach: We will leverage biobanked samples and extend follow-up of enrolled mother-child dyads in Dr. Bebell’s (K23AI138856) birth cohort, Dr. Bernstein’s adaptations of the Systems Serology platform to enteric organisms, and Dr. Mehta’s established multi’omics laboratory and data pipeline infrastructure to elucidate the effects of maternal HIV exposure and microbiome composition on child growth and immune development through age 5 via these Specific Aims: 1) Identify clinical metadata features associated with growth stunting in HEU children with fine resolution; 2) Characterize gut microbiome features associated with growth stunting in HEU children and establish mechanisms of host-microbe communication using metabolomics; 3) Define alterations in transplacental antibody transfer and breast milk antibody composition specific to pathogenic and non-pathogenic gut organisms in PPHIV and growth-stunted HEU children. Identifying HIV-related microbiome abnormalities and immune mechanisms of growth faltering has great potential to improve child health outcomes by informing vaccine strategies, microbiome therapy, and early intervention for children at high risk of poor growth outcomes.