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

项目摘要/摘要 每年有100多万新的结核病病例和239,000例与结核病相关的死亡病例发生在儿童中。 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)与结核病的发展，很少有研究探讨其发病机制。 儿童对结核病的艾滋病毒相关易感性。接触艾滋病毒的未感染儿童(HEU)在宫内暴露于 母体艾滋病毒和抗逆转录病毒疗法(ART)和这些暴露可能会影响随后的免疫 对结核分枝杆菌的答复。在艾滋病毒和结核病高流行的环境中，新生儿通常接受卡介苗接种。 在生命的最初几天内，这提供了一些保护，防止幼儿感染严重形式的结核病。 有趣的是，卡介苗接种也被认为具有非特定的益处，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功能有关。 对分枝杆菌和异源病原体的免疫反应，这种现象被称为“训练” 豁免权“。包括单核细胞和NK细胞在内的先天免疫细胞的表观遗传重新编程是一种 确定了促进卡介苗诱导训练性免疫的机制。母体接触HIV的影响 而婴儿感染HIV对接种卡介苗的婴儿诱导对结核分枝杆菌的训练性免疫尚未得到证实 描述。我们的研究将表征对分枝杆菌、辅因子的先天和获得性免疫反应。 例如可能影响免疫反应的ART，以及这些免疫反应对 儿童结核分枝杆菌感染的易感性。我们将检验以下假设：(1)母体感染艾滋病毒和婴儿 HIV感染通过先天免疫表观遗传重编程抑制对结核分枝杆菌训练性免疫的诱导 卡介苗接种婴儿的细胞；和(2)ART增强先天和获得性抗分枝杆菌免疫 HIV感染儿童的反应和抗分枝杆菌免疫缺陷将预测获得 结核分枝杆菌感染。利用肯尼亚临床特征良好的婴儿和儿童纵向队列，我们将 全面分析先天免疫的表型、功能、表观基因组和转录组 HEU、感染了HIV和未接触HIV的未感染婴儿的反应。然后我们将确定 修复HIV感染儿童的先天和适应性抗分枝杆菌免疫反应的ART 免疫相关性预测结核分枝杆菌感染的获得性。这些研究将提供前所未有的见解 探讨HIV对婴儿和儿童结核杆菌免疫的调节机制，并将为新的 在这些高危人群中进行结核病预防干预。

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.