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

由于抗逆转录病毒治疗的普及，围产期艾滋病毒传播率大幅下降 怀孕和哺乳期间。然而，这导致感染艾滋病毒的婴儿数量不断增加 暴露但未感染（iHEU）。 iHEU 显示出增强的炎症、免疫激活和免疫 疲惫可能是由肠道微生物群改变引起的。接触艾滋病毒也与受损有关 婴儿生长（发育迟缓）。多项研究表明，与 HIV 相比，iHEU 存在发育迟缓的证据 未暴露的婴儿 (iHU)。此外，营养不良研究已将慢性肠道炎症联系起来，这也 与肠道微生物群改变有关，导致婴儿生长受损。受损背后的机制 iHEU 的增长尚不清楚。 iHEU 中肠道炎症加剧可能与 发育迟缓。然而，iHEU 中的肠道微生物群是否会导致生长受损尚未得到正式测试。 除了生长之外，肠道微生物群还影响免疫发育。具体而言，早期的微生物群组成 生命印记持久的免疫学后果。 iHEU 显示出高传染性发病率，包括肠道感染 病原体。例如，研究表明 iHEU 表现出肠道致病性埃希氏菌的高患病率 大肠杆菌 (EPEC) 和隐孢子虫与未暴露的对应物进行比较。肠道微生物群已被证实 通过各种机制防止肠道病原体，包括定植抵抗和改变 粘膜免疫。 iHEU 中的肠道微生物群是否会增强对肠道病原体的易感性尚不清楚。 人类研究基于相关性，这限制了推断因果关系的能力。我们将使用无菌新生儿 小鼠模型研究 iHEU 中早期粪便微生物群在驱动这些临床中的因果作用 表型。此外，我们将使用 EPEC 新生小鼠模型来测试粪便微生物群之间的因果关系 和对肠道病原体的免疫力。我们假设 iHEU 生命早期的肠道微生物群导致 炎症、生长不良并损害对肠道病原体的免疫力。我们建议检验这个假设 具有以下具体目标。 目标 1：研究 iHEU 生命早期肠道微生物群是否引起肠道和全身炎症 婴儿期线性生长受损。 目标 2：研究 iHEU 的早期肠道微生物群是否会损害对肠道病原体的免疫力