The effect of HIV exposure and infection on immunity to TB in children

HIV暴露和感染对儿童结核病免疫力的影响

• 批准号: 10540681
• 负责人: Cheryl Liane Day
• 金额: $ 77.5万
• 依托单位: UNIVERSITY OF WASHINGTON
• 依托单位国家: 美国
• 财政年份: 2019
• 资助国家: 美国
• 起止时间: 2019-01-01 至 2024-12-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10540681
• 关键词: Activities of Daily Living; Address; Adult; Aggressive course; Antimycobacterial Agents; Bacille Calmette-Guerin vaccination; CD4 Positive T Lymphocytes; Cells; Cessation of life; Characteristics; Child; Childhood; Chromatin; Clinical; Cohort Studies; Cryopreservation; DNA; Data; Development; Disease; Epigenetic Process; Genus Mycobacterium; HIV; HIV Infections; HIV/TB; Heterochromatin; High Prevalence; Immune; Immune response; Immunity; Immunize; Infant; Infant Mortality; Infection; Inflammatory Response Pathway; Innate Immune Response; Kenya; Life; Longitudinal cohort; Mediating; Methylation; Morbidity - disease rate; Mycobacterium tuberculosis; Natural Killer Cells; Neonatal Mortality; Newborn Infant; Pediatric cohort; Peripheral Blood Mononuclear Cell; Phenotype; Populations at Risk; Predisposition; Prevalence; Reporting; Risk; Site; Specimen; T cell response; Technology; Testing; Training; Tuberculosis; Umbilical Cord Blood; Vaccination; Vaccinee; Virus; adaptive immune response; antiretroviral therapy; co-infection; cofactor; cohort; epigenome; infant infection; infection risk; insight; monocyte; mortality; mycobacterial; novel; pathogen; pathogenic bacteria; pathogenic fungus; pathogenic virus; pediatric human immunodeficiency virus; prenatal exposure; preventive intervention; repository; response; transcriptome; tuberculosis immunity

Project Summary / Abstract Over one million new cases of tuberculosis (TB) and 239,000 TB-related deaths occur in children each year. Despite evidence that HIV exposure in children is associated with a markedly increased risk of infection with Mycobacterium tuberculosis (Mtb) and development of TB disease, few studies have explored mechanisms for HIV-related susceptibility to TB in children. HIV-exposed uninfected children (HEU) are exposed in utero to both maternal HIV and anti-retroviral therapy (ART) and these exposures may influence subsequent immune responses to Mtb. In settings with high prevalence of HIV and TB, newborns typically receive BCG vaccination within the first few days of life, which confers some protection against severe forms of TB in young children. Interestingly, BCG vaccination has also been recognized to confer non-specific beneficial effects, including reduced neonatal and infant mortality. Moreover, vaccination with BCG is associated with enhanced innate immune responses to mycobacteria as well as heterologous pathogens, a phenomenon termed “trained immunity”. Epigenetic reprogramming of innate immune cells, including monocytes and NK cells, is one mechanism identified that contributes to BCG-induced trained immunity. The effect of maternal HIV exposure and infant HIV infection on induction of trained immunity to Mtb in BCG-vaccinated infants has not been described. Our studies will characterize innate and adaptive immune responses to mycobacteria, cofactors such as ART that may influence immune responses, and the implications of these immune responses for susceptibility to pediatric Mtb infection. We will test the hypotheses that (1) maternal HIV exposure and infant HIV infection dampen induction of trained immunity to Mtb via epigenetic reprogramming of innate immune cells in BCG-vaccinated infants; and (2) ART enhances innate and adaptive anti-mycobacterial immune responses in HIV-infected children and that deficits in anti-mycobacterial immunity will predict acquisition of Mtb infection. Using clinically-well characterized longitudinal cohorts of infants and children in Kenya, we will perform a comprehensive analysis of the phenotype, function, epigenome and transcriptome of innate immune responses in HEU, HIV-infected, and HIV-unexposed uninfected infants. We will then determine the capacity of ART to restore innate and adaptive anti-mycobacterial immune responses in HIV-infected children and identify immune correlates that predict acquisition of Mtb infection. These studies will provide unprecedented insights into mechanisms of HIV-associated modulation of immunity to Mtb in infants and children and will inform novel TB preventive interventions in these at-risk populations.

项目总结/摘要 每年有100多万新的结核病病例和239 000例与结核病有关的死亡发生在儿童中。 尽管有证据表明，儿童接触艾滋病毒与感染艾滋病毒的风险显著增加有关， 结核分枝杆菌（Mtb）和结核病的发展，很少有研究探讨了机制， 艾滋病毒相关的儿童结核病易感性。未感染艾滋病毒的儿童在子宫内暴露于 母亲艾滋病毒和抗逆转录病毒治疗（ART），这些暴露可能会影响随后的免疫 对MTB的回应在艾滋病毒和结核病高发地区，新生儿通常接受卡介苗接种 在生命的最初几天内，这为幼儿预防严重的结核病提供了一些保护。 有趣的是，BCG疫苗接种也被认为具有非特异性的有益作用，包括 降低新生儿和婴儿死亡率。此外，接种卡介苗与增强先天性 对分枝杆菌以及异源病原体的免疫应答，这种现象被称为“训练的 豁免权”。先天免疫细胞（包括单核细胞和NK细胞）的表观遗传重编程是一种 确定了有助于BCG诱导的训练免疫的机制。母亲接触艾滋病毒的影响 和婴儿HIV感染对卡介苗接种婴儿的Mtb训练免疫诱导的影响尚未得到证实。 介绍了我们的研究将描述先天性和适应性免疫反应的分枝杆菌，辅因子 如ART可能影响免疫反应，以及这些免疫反应对 儿童Mtb感染的易感性。我们将检验以下假设：（1）母亲艾滋病毒暴露和婴儿 HIV感染通过先天免疫的表观遗传重编程抑制对Mtb的训练免疫的诱导 细胞;（2）ART增强先天性和适应性抗分枝杆菌免疫 艾滋病毒感染儿童的免疫反应，抗分枝杆菌免疫缺陷将预测获得 结核病感染。使用临床特征良好的肯尼亚婴儿和儿童纵向队列，我们将 对先天免疫的表型、功能、表观基因组和转录组进行全面分析 高浓缩铀、艾滋病毒感染者和未接触艾滋病毒的未感染婴儿的反应。然后我们将确定 ART恢复HIV感染儿童的先天性和适应性抗分枝杆菌免疫应答， 免疫相关性预测获得结核分枝杆菌感染。这些研究将提供前所未有的见解 研究HIV相关的婴儿和儿童Mtb免疫调节机制，并将为新的 在这些高危人群中采取结核病预防干预措施。