Innate Immune Defects in HIV-Exposed Uninfected Infants: Effect on Respiratory Syncytial Virus Infection

暴露于 HIV 的未感染婴儿的先天免疫缺陷:对呼吸道合胞病毒感染的影响

基本信息

项目摘要

PROJECT SUMMARY/ABSTRACT HIV-exposed, uninfected (HEU) infants experience significantly higher rates of morbidity and mortality due to respiratory syncytial virus (RSV) infection compared to HIV-unexposed (HUU) infants. Natural killer (NK) cells and antigen-presenting cells (APCs) are innate immune cells that play a critical role in controlling RSV infection. We have previously identified abnormalities in NK cells and APCs from HEU infants, but it is not clear whether these abnormalities explain the increased severity of RSV disease observed in this population. This research seeks to address that knowledge gap and will also investigate which in utero exposures are responsible for immune dysfunction in HEU infants. This research is relevant to the mission of the NICHD because it will advance the understanding of immune cross-talk between the pregnant woman and fetus by studying the impact of maternal HIV infection on neonatal innate immune function. The central hypothesis of this proposal is that in utero exposure to the inflammatory environment associated with maternal HIV infection induces DNA methylation changes in innate immune cells that alter NK cell and APC function, and ultimately impair the response to RSV infection. This hypothesis will be tested through the following specific aims: 1) To compare the innate immune response to RSV infection between HEU and HUU infants using an in vitro model of human respiratory infection; 2) To determine the effect of exposure to an environment enriched in inflammatory cytokines on neonatal innate immune cell function; 3) To identify differences in DNA methylation and RNA expression in NK cells and APCs between HEU and HUU infants and determine the effect of in vitro cytokine exposure on the epigenetic and transcriptomic profile of these cells. Aim 1 will be investigated using an innovative respiratory epithelial and endothelial co-culture system along with HEU and HUU cord or peripheral blood mononuclear cells. In Aim 2, HUU NK cells and APCs will be incubated with inflammatory cytokines to simulate HEU infants’ in utero conditions. Aim 3 will generate the first description of the epigenome and transcriptome of HEU compared with HUU infants, using robust techniques including DNA methylation arrays and single cell RNA sequencing. This approach is innovative because it: 1) allows the first investigation of the impact of HEU immune dysregulation on RSV pathogenesis, and 2) may identify the mechanism for immune dysregulation in HEU infants. This project is significant because it has potential to improve health outcomes for the more than 1 million HEU infants born each year. Complimentary to the proposed research plan, a five-year mentored career development training plan has been devised that incorporates didactic learning in genomic data analysis and hands-on training in virology and immunology laboratory skills. The candidate is co-mentored by internationally recognized experts in the fields of virology, immunology, and genomics/bioinformatics. The candidate’s long- term career goal is to become an independent investigator studying the immune effects of HIV exposure.
项目概要/摘要 暴露于 HIV 的未感染 (HEU) 婴儿的发病率和死亡率明显更高 与未暴露于艾滋病毒(HUU)的婴儿相比,呼吸道合胞病毒(RSV)感染的风险更高。自然杀伤 (NK) 细胞 抗原呈递细胞 (APC) 是先天免疫细胞,在控制 RSV 感染中发挥着关键作用。 我们之前已经发现 HEU 婴儿的 NK 细胞和 APC 存在异常,但尚不清楚是否 这些异常现象解释了在该人群中观察到的 RSV 疾病严重程度的增加。这项研究 力求弥补这一知识差距,并将调查哪些子宫内暴露是造成这种情况的原因 HEU 婴儿的免疫功能障碍。这项研究与 NICHD 的使命相关,因为它将推进 通过研究孕妇和胎儿之间的免疫串扰的影响来了解 母亲HIV感染对新生儿先天免疫功能的影响。 该提案的中心假设是,在子宫内暴露于与炎症相关的环境 母体 HIV 感染会引起先天免疫细胞 DNA 甲基化变化,从而改变 NK 细胞和 APC 功能,并最终损害对 RSV 感染的反应。该假设将通过以下方式进行检验 具体目标: 1) 使用 HEU 和 HUU 婴儿对 RSV 感染的先天免疫反应进行比较 人类呼吸道感染的体外模型; 2) 确定暴露于环境的影响 富含炎症细胞因子对新生儿先天免疫细胞功能的影响; 3) 识别DNA差异 HEU 和 HUU 婴儿之间 NK 细胞和 APC 的甲基化和 RNA 表达并确定效果 体外细胞因子暴露对这些细胞的表观遗传和转录组谱的影响。将调查目标 1 使用创新的呼吸道上皮和内皮共培养系统以及 HEU 和 HUU 线或 外周血单个核细胞。在目标 2 中,HUU NK 细胞和 APC 将与炎症细胞一起孵育 细胞因子模拟 HEU 婴儿在子宫内的条件。目标 3 将生成表观基因组的第一个描述 使用包括 DNA 甲基化在内的强大技术,将 HEU 和转录组与 HUU 婴儿进行比较 阵列和单细胞 RNA 测序。 这种方法具有创新性,因为它:1) 可以首次研究 HEU 免疫的影响 RSV 发病机制失调,2) 可能确定 HEU 中免疫失调的机制 婴儿。该项目意义重大,因为它有可能改善超过 100 万人的健康状况 每年出生的 HEU 婴儿。对拟议的研究计划的补充,为期五年的指导职业 制定了发展培训计划,将教学学习纳入基因组数据分析和 病毒学和免疫学实验室技能的实践培训。候选人由国际人士共同指导 病毒学、免疫学和基因组学/生物信息学领域的公认专家。候选人的长期 短期职业目标是成为一名独立研究者,研究艾滋病毒暴露的免疫影响。

项目成果

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Christiana Elizabeth Smith-Anderson其他文献

Christiana Elizabeth Smith-Anderson的其他文献

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{{ truncateString('Christiana Elizabeth Smith-Anderson', 18)}}的其他基金

Innate Immune Defects in HIV-Exposed Uninfected Infants: Effect on Respiratory Syncytial Virus Infection
暴露于 HIV 的未感染婴儿的先天免疫缺陷:对呼吸道合胞病毒感染的影响
  • 批准号:
    9926674
  • 财政年份:
    2020
  • 资助金额:
    $ 16.2万
  • 项目类别:
Innate Immune Defects in HIV-Exposed Uninfected Infants: Effect on Respiratory Syncytial Virus Infection
暴露于 HIV 的未感染婴儿的先天免疫缺陷:对呼吸道合胞病毒感染的影响
  • 批准号:
    10563218
  • 财政年份:
    2020
  • 资助金额:
    $ 16.2万
  • 项目类别:
Innate Immune Defects in HIV-Exposed Uninfected Infants: Effect on Respiratory Syncytial Virus Infection
暴露于 HIV 的未感染婴儿的先天免疫缺陷:对呼吸道合胞病毒感染的影响
  • 批准号:
    10117083
  • 财政年份:
    2020
  • 资助金额:
    $ 16.2万
  • 项目类别:

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