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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：
10223400
负责人：
Rana Chakraborty
金额：
$ 16.76万
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 2024-07-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/10223400
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 fetal immunity 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.

项目摘要一项新的证据表明，人类的发病率和死亡率正在增加免疫缺陷病毒(HIV)暴露的未感染婴儿(HEU)与未感染HIV的婴儿的比较女性(HUU)。随着高浓缩铀儿童人口以每年100万英镑的速度增长，确定了可修改的机制在这些差异的背后是一个全球卫生优先事项。几项研究表明，在怀孕期间合并母体HIV感染，暴露于共病原体诱导胎盘免疫激活，这可能会改变胎盘信号，影响胎儿免疫力。其中一种混合感染是人类巨细胞病毒。 (巨细胞病毒)。流行病学研究表明，人巨细胞病毒混合感染可能与HIV疾病有关。进展和死亡率增加。最近，我们发现人胎盘绒毛中存在CD8+T细胞。与来自南非的胎盘相比，怀孕、感染艾滋病毒(PWLHIV)和巨细胞病毒感染的南非妇女人巨细胞病毒阳性的未感染HIV的妇女。我们假设有招募和移民母体来源的巨细胞病毒特异性CD8+T细胞从子宫蜕膜到胎盘绒毛。我们假设滋养层细胞促进抗原特异性CD8+T细胞向胎儿绒毛室迁移，这进一步加剧了炎症级联，促进了滋养层细胞的凋亡。在……里面为了验证我们的假设，我们将招募孕妇参加南部开普敦的产前护理非洲被分成两组：1)艾滋病毒/巨细胞病毒合并感染的孕妇；2)仅感染巨细胞病毒的妇女。我们将确定这些浸润性T细胞的来源、表型和表位特异性，并检查滋养层细胞在将这些T细胞招募到绒毛间隙中的作用。拟议的研究将提供一个对母亲孕期HIV/HCMV混合感染的体内影响的更深层次的概念理解胎盘免疫力。这些研究可以促进免疫调节和抗病毒药物的发展。分别针对炎症和巨细胞病毒的治疗可能改善HEU婴儿的临床结局来自艾滋病毒和巨细胞病毒共同感染的孕妇。

项目成果

期刊论文数量（5）

专著数量（0）

科研奖励数量（0）

会议论文数量（0）

专利数量（0）

Host-Viral Interactions at the Maternal-Fetal Interface. What We Know and What We Need to Know.

母体-胎儿界面的宿主-病毒相互作用。

DOI：
10.3389/fviro.2022.833106
发表时间：
2022
期刊：
Frontiers
影响因子：
1.2
作者：
Girsch,JamesH;MejiaPlazas,MariaC;Olivier,Amanda;Farah,Mohamed;Littlefield,Dawn;Behl,Supriya;Punia,Sohan;Sakemura,Reona;Hemsath,JackR;Norgan,Andrew;Enninga,ElizabethAL;Johnson,EricaL;Chakraborty,Rana
通讯作者：
Chakraborty,Rana

Turning Discoveries into Treatments: Immunology in Africa.