Influence of Early Life Gut Microbiota of HIV-Exposed Uninfected Infants on Inflammation, Growth and Immunity to Enteric Pathogens

暴露于 HIV 的未感染婴儿的早期肠道微生物群对炎症、生长和肠道病原体免疫的影响

• 批准号: 10757205
• 负责人: Donald Nyangahu
• 金额: $ 24.61万
• 依托单位: SEATTLE CHILDREN'S HOSPITAL
• 依托单位国家: 美国
• 财政年份: 2023
• 资助国家: 美国
• 起止时间: 2023-08-03 至 2025-07-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10757205
• 关键词: Acquired Immunodeficiency Syndrome; Address; Age; Antibodies; Area; Automobile Driving; Bacteremia; Bacteria; Biological Assay; Breast Feeding; Cells; Child; Childhood; Chronic; Clinical; Colon; Cryptosporidium; Development; Diarrhea; Disease; Duodenum; Enteral; Enzyme-Linked Immunosorbent Assay; Escherichia coli Infections; Etiology; Euthanasia; Exhibits; Feces; Functional disorder; Future; Germ-Free; Growth; HIV; HIV-exposed uninfected infant; High Prevalence; Human; Humoral Immunities; Immune; Immune System Diseases; Immune response; Immunity; Immunologics; Impairment; Infant; Infection; Inflammation; Intervention; Intestines; Investigation; Knowledge; Lamina Propria; Lead; Life; Link; Malnutrition; Measures; Morbidity - disease rate; Mucosal Immunity; Mus; Neonatal; Nigeria; Oral; Outcome; Plasma; Play; Pneumonia; Population; Predisposition; Pregnancy; Probiotics; Recurrence; Research; Risk; Risk Factors; Role; Sampling; Severities; Signal Transduction; T-Lymphocyte; Testing; Therapeutic Intervention; Viral; Weaning; adaptive immunity; antiretroviral therapy; clinical phenotype; cohort; colonization resistance; enteric infection; enteric pathogen; enteropathogenic Escherichia coli; exhaustion; falls; fecal transplantation; gut bacteria; gut inflammation; gut microbiota; high risk; ileum; immune activation; imprint; improved; infancy; inflammatory marker; microbial; microbiota; mortality; mouse model; neonatal mice; pathogen; perinatal HIV; pup; single-cell RNA sequencing; systemic inflammatory response; transcriptome; transmission process

Rates of perinatal HIV transmission have fallen substantially due to increased access to antiretroviral therapy during pregnancy and breastfeeding. However, this has led to a growing population of infants who are HIV- exposed but uninfected (iHEU). iHEU display heightened inflammation, immune activation and immune exhaustion potentially driven by their altered gut microbiota. HIV exposure has also been linked to impaired growth (stunting) in infants. Multiple studies have shown evidence of stunting in iHEU compared to HIV unexposed infants (iHU). In addition, malnutrition studies have linked chronic intestinal inflammation, which also associated with gut microbiota alteration, in infants to impaired growth. The mechanism(s) behind impaired growth in iHEU are not understood. It is plausible that heightened intestinal inflammation in iHEU may associate with stunting. However, whether the gut microbiota in iHEU causes impaired growth has not been formally tested. Beyond growth, the gut microbiota impacts immune development. Specifically, microbiota composition early in life imprint lasting immunological consequences. iHEU display high infectious morbidity including to enteric pathogens. For example, studies have shown that iHEU exhibit high prevalence of enteropathogenic Escherichia coli (EPEC) and Cryptosporidium spp compared to unexposed counterparts. The gut microbiota has been shown to protect against enteric pathogens via various mechanisms including colonization resistance and alteration of mucosal immunity. Whether gut microbiota in iHEU enhance susceptibility to enteric pathogens is unknown. Human studies are based on correlations which limit ability to infer causation. We will utilize a germ-free neonatal mouse model to investigate the causal role of the early stool microbiota in iHEU in driving these clinical phenotypes. In addition, we will use a neonatal mouse model of EPEC to test causality between stool microbiota and immunity to enteric pathogens. We hypothesize that the gut microbiota of iHEU early in life causes inflammation, poor growth and impairs immunity to enteric pathogens. We propose to test this hypothesis with the following specific aims. Aim 1: To investigate whether the early life gut microbiota of iHEU causes intestinal and systemic inflammation and impaired linear growth during infancy. Aim 2: To investigate whether the early life gut microbiota of iHEU impairs immunity to enteric pathogens

由于获得抗逆转录病毒疗法的增加，围产期艾滋病毒传播的发生率大大下降了 在怀孕和母乳喂养期间。但是，这导致了越来越多的艾滋病毒的婴儿 暴露但未感染（IHEU）。 IHEU显示出炎症，免疫激活和免疫 疲惫可能是由于其肠道微生物群改变的驱动。艾滋病毒的暴露也与受损 婴儿的生长（发育迟缓）。多项研究表明，与HIV相比，IHEU发育迟缓的证据 未暴露婴儿（IHU）。此外，营养不良研究已将慢性肠道炎症联系起来，这也是 与肠道微生物群的改变相关，婴儿的生长受损。障碍背后的机制 IHEU的增长尚不理解。 IHEU的肠道炎症加剧可能会关联是合理的 发育迟缓。但是，IHEU中的肠道微生物群是否会导致生长受损受损。 除了增长之外，肠道菌群还会影响免疫发育。具体而言，菌群成分早期 生命烙印持续的免疫学后果。 IHEU表现出高感染性发病率，包括肠 病原体。例如，研究表明，iHEU表现出肠病的高流行率 与未暴露的对应物相比，大肠杆菌（EPEC）和隐孢子虫属。肠道菌群已显示 通过各种机制来防止肠道病原体，包括定殖抗性和改变 粘膜免疫。 IHEU中的肠道微生物群是否增强对肠道病原体的敏感性尚不清楚。 人类研究基于限制推断因果关系的能力的相关性。我们将利用无菌新生儿 小鼠模型研究早期粪便微生物群在IHEU驱动这些临床方面的因果作用 表型。此外，我们将使用EPEC的新生小鼠模型来测试粪便微生物群之间的因果关系 对肠道病原体的免疫力。我们假设生命早期Iheu的肠道菌群 炎症，生长不良并损害对肠道病原体的免疫力。我们建议检验这一假设 具有以下特定目标。 目的1：研究早期生命的肠道菌群是否会引起肠道和全身性炎症 和婴儿期线性生长受损。 目标2：研究早期生命的肠道菌群是否会损害肠道病原体的免疫力