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

暴露于艾滋病毒的未感染儿童中微生物组驱动的免疫变化和生长迟缓

• 批准号: 10698459
• 负责人: Lisa M Bebell
• 金额: $ 81.05万
• 依托单位: MASSACHUSETTS GENERAL HOSPITAL
• 依托单位国家: 美国
• 财政年份: 2023
• 资助国家: 美国
• 起止时间: 2023-05-11 至 2028-01-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10698459
• 关键词: Address; Age; Antibodies; Antibody Response; B-Lymphocyte Subsets; B-Lymphocytes; Biological; Birth; Blood; Breast Feeding; Caring; Characteristics; Child; Child Health; Childhood; Clinical; Communicable Diseases; Communication; Data; Defect; Development; Diarrhea; Diet; Disease model; Early Intervention; Early identification; Enrollment; Enteral; Environmental Exposure; Epidemiology; Fc Receptor; Feces; Food; Goals; Growth; HIV; Health; Homeostasis; Human Milk; Immune; Immune response; Immune system; Immunity; Immunoglobulin A; Immunoglobulin G; Immunology; Infection; Inflammatory; Infrastructure; Innate Immune Response; Laboratories; Link; Longitudinal cohort; Maternally-Acquired Immunity; Measures; Metadata; Metagenomics; Microbe; Morbidity - disease rate; Mothers; Neonatal; Newborn Infant; Nutritional status; Organism; Outcome; Pathogenicity; Pathway interactions; Persons; Plasma; Play; Predisposition; Pregnancy; Proteobacteria; Public Health; Recurrence; Reporting; Research; Research Personnel; Resolution; Risk; Sampling; Serology; Serum; Shapes; Source; System; T-Lymphocyte; Time; Uganda; Umbilical cord structure; United States National Institutes of Health; Vaccination; Viral; Virulence; Volatile Fatty Acids; Work; antibody transfer; antimicrobial; antiretroviral therapy; biobank; burden of illness; cohort; comorbidity; data pipeline; diarrheal disease; follow-up; gut microbiome; high risk; improved; improved outcome; infant gut microbiome; innovation; metabolomics; microbial; microbiome; microbiome composition; monocyte; mortality; novel; nutrition; pathobiont; pathogen; peer; poor health outcome; pregnant; prospective; receptor; receptor binding; recurrent infection; species difference; stool sample; vaccination strategy; vaccine response; vaccine strategy

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.

项目概要 尽管怀孕期间接受抗逆转录病毒治疗 (ART) 的机会越来越多，但每年出生的超过 100 万儿童 暴露于 HIV 病毒但未感染 (HEU) 的 HIV 感染孕妇 (PPHIV) 的感染风险仍高出 2 倍以上 生长发育迟缓和感染发病率高于未接触艾滋病毒的儿童。 人们对健康结果知之甚少，越来越多的证据表明微生物组发育异常 可能发挥关键作用。然而，其机制仍然难以捉摸，需要更好的机制理解。 我们的首要目标是确定临床、环境、饮食和流行病学。 与 HEU 儿童生长迟缓相关的特征，表征宿主微生物的机制 沟通，并将肠道微生物组特征与生长发育不良的 HEU 儿童的免疫发育联系起来 为此，我们将利用来自生物库的数据和新收集的样本。 乌干达正在进行的前瞻性纵向出生队列研究将生长迟缓、腹泻疾病负担和 微生物驱动的 HEU 儿童免疫力变化的不良临床结果：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 免疫特征发展和儿童生长发育迟缓是新颖的、高度相关的并且在概念上具有创新性。 我们提出的研究的独特优势包括 1) 同时比较 HIV 暴露样本 - 未暴露组以尽量减少混杂，2) 丰富的临床、流行病学和环境暴露 充分表征的纵向队列中的数据，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拥有专业知识 （Bebell）；免疫学（Alter、Bernshtein）、多组学（Mehta、Chan、Huttenhower）已经做好了完成这项工作的准备 方法：我们将利用生物库样本并扩大对已登记的母子二人组的随访。 Bebell 博士 (K23AI138856) 出生队列，Bernstein 博士对系统血清学平台的肠溶适应 生物体，以及 Mehta 博士建立的多组学实验室和数据管道基础设施，以阐明 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 5 岁以下具体目标：1) 识别与 HEU 生长迟缓相关的临床元数据特征 具有精细分辨率的儿童；2) 表征与 HEU 生长迟缓相关的肠道微生物组特征 儿童并利用代谢组学建立宿主-微生物通讯机制；3）定义 经胎盘抗体转移和针对致病性和非致病性的母乳抗体组合物 PPHIV 和生长发育迟缓的 HEU 儿童的肠道微生物识别与 HIV 相关的微生物组异常和 生长迟缓的免疫机制具有通过告知儿童改善儿童健康结果的巨大潜力 针对生长不良高风险儿童的疫苗策略、微生物组治疗和早期干预。