MECHANISMS LEADING TO ADVERSE BIRTH OUTCOMES IN SOUTH AFRICAN HIV-INFECTED WOMEN

导致南非艾滋病毒感染妇女不良分娩结果的机制

基本信息

批准号：
10388379
负责人：
Clive Maurice Gray
金额：
$ 33.44万
依托单位：
STELLENBOSCH UNIVERSITY
依托单位国家：
美国
项目类别：
财政年份：
2020
资助国家：
美国
起止时间：
2020-04-03 至 2025-03-31
项目状态：
未结题

来源：
https://reporter.nih.gov/project-details/10388379
关键词：
16S ribosomal RNA sequencing Africa South of the Sahara African Anti-Retroviral Agents Area Birth Birth Weight Cells Cellular Immunity Cellular Stress Child Health Cohort Studies Collaborations Data Decidua Development Epidemic Event Female genitalia Fetal Development Flow Cytometry Funding Gene Expression Gestational Age HIV HIV Infections HIV-exposed uninfected infant Image Immune Immunity Immunologics Impairment Infant Infant Health Inflammation Inflammatory Investigation Kenya Lead Life Link Location Low Birth Weight Infant Lung Mass Spectrum Analysis Maternal-Fetal Exchange Measurement Measures Metabolic Metabolic Marker Metabolic Pathway Microbiology Morbidity - disease rate Mothers Neonatal Mortality Neurologic Newborn Infant Outcome Pathway interactions Persons Pharmaceutical Preparations Pharmacotherapy Phase Phenotype Placenta Population Postdoctoral Fellow Postpartum Period Pregnancy Pregnant Women Premature Birth Premature Infant Premature Labor Prevention Measures Proxy Regulatory T-Lymphocyte Risk Risk Factors Sampling Small for Gestational Age Infant South Africa South African T cell response T-Lymphocyte Tissues Training Underrepresented Populations United States National Institutes of Health Universities Vaccines Vagina Villous Woman Work adverse birth outcomes adverse pregnancy outcome case control cohort doctoral student experience immunoregulation in utero metabolome microbial microbial community microbiota metabolites neonate perinatal HIV premature prospective rRNA Genes reproductive tract study population transcriptome sequencing transmission process ultrasound vaccine immunogenicity vaginal microbiome vaginal microbiota

项目摘要

Pre-term birth (PTB) is a major cause of neonatal mortality worldwide, associated with high morbidity due to infectious and other complications. Identifying risk factors for adverse birth outcomes, as well as the likely causes, will facilitate prevention measures to mitigate these outcomes. Sub-Saharan Africa (SSA) has the highest burden of these adverse pregnancy outcomes, and also bears the brunt of the global HIV epidemic, with over 33 million people living with HIV. Untreated maternal HIV infection has been shown to be associated with spontaneous PTB in some but not all studies. Antiretroviral (ARV) drug treatment during pregnancy dramatically reduces perinatal HIV transmission but has also been linked to adverse birth outcomes. Here, we will utilize our completed and ongoing cohorts of pregnant women in Cape Town, South Africa, and build on our previous phase 1 NIH-SAMRC funding (R21 HD083344), to study the impact of HIV/ARV exposure on female genital tract microbiology and metabolome and the relationship with placental immune pathways that impact infant health: prematurity and post-partum vaccine immunogenicity. The specific aims are 1) To identify vaginal microbial and metabolic markers for adverse birth outcomes in HIV-infected women. Here, we hypothesis that PTB is associated with specific vaginal microbial communities leading to alterations in metabolic pathways that can result in cell stress and subsequent placental inflammation. We will use 16S rRNA sequencing and unbiased mass spectrometry to measure vaginal microflora and metabolites during gestation. 2) To interrogate immune cell subsets and gene expression pathways in placental decidual and villous tissue which lead to PTB in HIV-infected pregnancies. We hypothesize that placental T cells are skewed away from regulatory towards inflammatory and activated states through HIV/ARV exposure, leading to increased risk of preterm labor. We will use a combination of multiparameter flow cytometry, imaging and RNAseq to characterize T cell populations, their tissue location and function. Placentas from HIV-uninfected women will be used as controls. 3) To identify decidual immune cells and gene expression pathways that influence infant cellular immunity. We hypothesize that inflammatory conditions at the fetal-maternal interface contribute to the development of compromised vaccine-specific immunity post-partum. We will measure infant BCG T cell responses in the first two months of life and relate this to placental cell phenotype, function and gene expression in mother-infant pairs. Identifying risk factors for adverse birth outcomes, as well as the likely causes, will facilitate prevention measures to mitigate these outcomes. ! !

预期出生（PTB）是全球新生儿死亡率的主要原因，与高发病率有关传染性和其他并发症。确定不良出生结果的危险因素以及可能原因，将促进预防措施减轻这些结果。撒哈拉以南非洲（SSA）有这些不良怀孕结果的最高负担，也承受着全球艾滋病毒流行的首当其冲，有超过3300万人感染了艾滋病毒。未经治疗的母体HIV感染已被证明是相关的在某些但并非所有研究中都有自发的PTB。怀孕期间抗逆转录病毒（ARV）药物治疗大大减少了围产期HIV的传播，但也与不良的出生结果有关。在这里，我们将利用我们在南非开普敦的完整和持续的孕妇，并以我们以前的1阶段NIH-SAMRC资金（R21 HD083344），研究HIV/ARV暴露对女性生殖道微生物学和代谢组以及与胎盘免疫途径的关系影响婴儿健康：早产和后产后疫苗免疫原性。具体目的是1）确定艾滋病毒感染妇女的不良出生结果的阴道微生物和代谢标记。在这里，我们假设PTB与特定的阴道微生物群落有关，导致改变代谢途径会导致细胞应激和随后的胎盘炎症。我们将使用16s rRNA测序和公正的质谱法，以测量阴道菌群和代谢物。妊娠。 2）审问胎盘decial和在HIV感染的妊娠中导致PTB的绒毛组织。我们假设胎盘T细胞是通过HIV/ARV暴露，从调节性偏向炎症和激活状态，领先增加早产的风险。我们将结合多参数流式细胞仪，成像和 RNASEQ表征T细胞群体，其组织位置和功能。来自HIV未感染的胎盘妇女将被用作对照。 3）鉴定判断性免疫细胞和基因表达途径影响婴儿细胞免疫。我们假设胎儿界面处的炎症条件有助于产后疫苗特异性免疫受损的发展。我们将测量婴儿 BCG T细胞反应在生命的前两个月，并将其与胎盘细胞表型，功能和母亲对中的基因表达。确定不良出生结果的危险因素以及可能原因，将促进预防措施减轻这些结果。呢呢