Mechanisms by which trophoblasts recruit T cells to the placental villi during maternal HIV and CMV co-infection

母体 HIV 和 CMV 合并感染期间滋养层将 T 细胞募集至胎盘绒毛的机制

基本信息

批准号：
10080877
负责人：
Rana Chakraborty
金额：
$ 22.28万
依托单位：
MAYO CLINIC ROCHESTER
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：
2020-08-01 至 2022-07-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/10080877
关键词：
Activities of Daily Living Address Affect Alleles Anti-Retroviral Agents Antigens Antiviral Therapy Apoptosis Apoptotic Autologous Blood CD3 Antigens CD8-Positive T-Lymphocytes CD8B1 gene Cells Cesarean section Cessation of life Child Chorionic villi Clinical Color Cytomegalovirus DNA Data Decidua Development Disease Progression Enrollment Epitopes Etiology Exposure to Fetus Fluorescent in Situ Hybridization Gene Expression Profile HIV HIV Infections HIV Seropositivity HIV-exposed uninfected infant HLA Antigens Health Health Priorities Human Image Immunity Infant Infection Infiltration Inflammation Inflammation Mediators Inflammatory Knowledge Link Location Major Histocompatibility Complex Maternal Health Mediator of activation protein Memory Migration Assay Morbidity - disease rate Mothers Movement Outcome Paraffin Embedding Pathology Phenotype Placenta Polymerase Chain Reaction Population Pregnancy Pregnant Women Prenatal care Production Prospective cohort Proteins Publishing Reporting Research Infrastructure Role Signal Transduction South Africa South African Specificity T-Cell Receptor T-Lymphocyte Testing Time Tissues Universities Uterus Villous Villus Virus Virus Replication Woman Zika Virus chemokine co-infection cohort comorbidity cytokine cytotrophoblast epidemiology study experience fetal global health immune activation immunomodulatory therapies improved in vivo keratin CK7 macrophage male migration mortality pathogen pregnant recruit response single-cell RNA sequencing targeted treatment trophoblast

项目摘要

PROJECT ABSTRACT An emerging body of evidence suggests there is increased morbidity and mortality among human immunodeficiency virus (HIV)-exposed uninfected infants (HEUs) compared to infants born to HIV-uninfected women (HUU). With the HEU child population increasing at >1 million/year, identifying modifiable mechanisms underlying these disparities is a global health priority. Several studies suggest that during pregnancy complicated by maternal HIV infection, exposure to co-pathogens induces placental immune activation, which may alter placental signaling affecting fetal immunity. One such co-infection is human cytomegalovirus (HCMV). Epidemiologic studies have reported that HCMV co-infection may contribute to HIV disease progression and increased mortality. We recently identified the presence of CD8+ T cells in placental villi from pregnant, South African women living with HIV (PWLHIV) and HCMV co-infection, compared to placentae from HIV-uninfected women who were HCMV positive. We hypothesize that there is recruitment and migration of maternally-derived HCMV-specific CD8+ T cells from the uterine decidua to placental villi. We posit that trophoblasts promote migration of antigen-specific CD8+ T cells into the fetal villi compartment, which further exacerbates the inflammatory cascade and promotes apoptosis of trophoblast cells. In order to validate our hypothesis, we will enroll pregnant women attending prenatal care in Cape Town, South Africa, into two groups: 1) HIV/HCMV co-infected pregnant women; and 2) women with HCMV infection only. We will determine the origin, phenotype and epitope specificity of these infiltrating T cells, as well as examine the role of trophoblasts in recruiting these T cells into the villous space. The proposed studies will provide a deeper conceptual understanding of the in vivo effects of maternal HIV/HCMV co-infection during pregnancy on placental immunity. These studies could facilitate the development of immunomodulatory and antiviral therapies targeting inflammation and HCMV, respectively, which may improve clinical outcomes in HEU infants from HIV- and HCMV-coinfected pregnant women.

项目摘要越来越多的证据表明，人类的发病率和死亡率有所增加暴露于免疫缺陷病毒 (HIV) 的未感染婴儿 (HEU) 与未感染 HIV 所生婴儿的比较妇女（HUU）。随着 HEU 儿童人口每年增加超过 100 万，确定可修改的机制这些差异的背后是全球卫生优先事项。多项研究表明，在怀孕期间由于母体艾滋病毒感染，暴露于共同病原体会诱导胎盘免疫激活，从而导致胎盘免疫激活。可能会改变影响胎儿免疫力的胎盘信号。其中一种共同感染是人类巨细胞病毒（HCMV）。流行病学研究表明，HCMV 合并感染可能导致 HIV 疾病进展和死亡率增加。我们最近在胎盘绒毛中发现了 CD8+ T 细胞的存在与感染 HIV (PWLHIV) 和 HCMV 双重感染的南非孕妇相比，胎盘 HCMV 阳性但未感染 HIV 的女性。我们假设存在招募和迁移母体来源的 HCMV 特异性 CD8+ T 细胞从子宫蜕膜到胎盘绒毛。我们假设滋养层促进抗原特异性 CD8+ T 细胞迁移到胎儿绒毛区室，进一步加剧炎症级联反应并促进滋养层细胞凋亡。在为了验证我们的假设，我们将招募在南部开普敦接受产前护理的孕妇非洲，分为两组：1）HIV/HCMV 合并感染的孕妇； 2) 仅感染 HCMV 的女性。我们将确定这些浸润 T 细胞的起源、表型和表位特异性，并检查滋养层在将这些 T 细胞招募到绒毛空间中的作用。拟议的研究将提供对孕期母亲 HIV/HCMV 混合感染的体内影响有更深入的概念理解关于胎盘免疫。这些研究可以促进免疫调节和抗病毒药物的开发分别针对炎症和 HCMV 的疗法可能会改善 HEU 婴儿的临床结果来自同时感染 HIV 和 HCMV 的孕妇。