CMV infection impact on placental immunometabolism and fetal immunity

CMV感染对胎盘免疫代谢及胎儿免疫力的影响

• 批准号: 10536197
• 负责人: Amitinder Kaur
• 金额: $ 42.47万
• 依托单位: TULANE UNIVERSITY OF LOUISIANA
• 依托单位国家: 美国
• 财政年份: 2022
• 资助国家: 美国
• 起止时间: 2022-09-01 至 2025-06-30
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10536197
• 关键词: Acute; Adaptive Immune System; Affect; Amniotic Fluid; Animal Model; B-Lymphocytes; Biological; Biological Assay; Biological Markers; Biological Response Modifiers; Birth; Blood; Bone Marrow; Breeding; Cells; Cellular Immunology; Cesarean section; Child; Childhood; Chronic; Communicable Diseases; Comparative Study; Cytomegalovirus; Cytomegalovirus Infections; Enrollment; Epigenetic Process; Epilepsy; Exposure to; Fetal Development; Fetal Tissues; First Pregnancy Trimester; Flow Cytometry; Genetic; Genus Hippocampus; Grant; Human; Immune; Immune system; Immunocompetent; Immunologics; Impaired cognition; Infant; Infection; Inflammation; Inflammatory; Knowledge; Leukocytes; Life; Lymphocyte; Macaca; Macaca mulatta; Maternal Exposure; Maternal-Fetal Exchange; Maternally-Acquired Immunity; Mediating; Metabolic; Metabolic Pathway; Metabolism; Mitogens; Modeling; Modification; Monitor; Monozygotic twins; Mus; Natural Immunity; Natural Killer Cells; Newborn Infant; Outcome; PTPRC gene; Phenotype; Population; Population Study; Pregnancy; Primary Infection; Primates; Regulatory T-Lymphocyte; Reporting; Research; Rhesus; Role; Second Pregnancy Trimester; Seroprevalences; Spleen; Stains; T-Lymphocyte; Thymus Gland; Vaccination; Virus Diseases; Woman; XCL1 gene; adaptive immunity; congenital cytomegalovirus; congenital infection; cytokine; disability; fetal; fetal blood; fetal immunity; fetal programming; hearing impairment; immune function; imprint; in utero; insight; metabolic abnormality assessment; metabolomics; monocyte; motor impairment; nonhuman primate; novel; pregnant; prospective; seropositive; transcriptome sequencing; transcriptomics; transmission process; young adult

PROJECT SUMMARY/ABSTRACT Cytomegalovirus (CMV) is a ubiquitous species-specific betaherpesvirus that results in life-long persistent asymptomatic infection in an immunocompetent host. Human CMV (HCMV) is the most common infectious cause of congenital infection, complicating 40,000 births in the U.S. annually. In utero CMV transmission occurs in 33-50% of pregnant CMV-seronegative women with primary infection; it also occurs after non-primary infection in pregnant CMV-seropositive women so that regions of high CMV seroprevalence account for a major part of the global burden of congenital CMV. Studies in mice and humans have shown that CMV has profound effects on both the innate and adaptive immune system. However, there is a gap in knowledge of when CMV imprints the immune system and whether maternal CMV infection during pregnancy can affect fetal development and immunity even in the absence of CMV transmission. In this grant, our aim is to study the effect of maternal exposure to CMV infection on fetal immunity using a biologically relevant rhesus macaque nonhuman primate (NHP) animal model of HCMV. We hypothesize that maternal exposure to CMV infection during pregnancy induces perturbation of cellular metabolism that adversely affect immune cell populations utilizing common metabolic pathways, leading to (i) hitherto unrecognized impact of CMV-mediated metabolic dysregulation on innate and adaptive immunity at the maternal-fetal interface, and (ii) epigenetic modifications and functional effects on fetal T and B lymphocytes, monocytes and NK cells. We will utilize a combined approach of cellular immunology assays, transcriptomics and metabolomics to investigate the effect of CMV infection on placental immunometabolism and fetal immunity in the NHP model. Our specific aims are: #1. To investigate the effect of chronic maternal CMV infection on placental immunometabolism and fetal immunity; and #2. To determine the effect of experimental primary CMV infection during pregnancy on placental immunometabolism and fetal immunity.

项目总结/摘要 巨细胞病毒（CMV）是一种普遍存在的物种特异性β疱疹病毒，其导致终身持续性的 免疫活性宿主无症状感染。人巨细胞病毒（HCMV）是最常见的感染性 这是一种先天性感染的原因，每年在美国有4万例分娩。子宫内CMV传播发生 在33-50%的CMV血清阴性孕妇原发感染;它也发生在非原发感染后， CMV血清阳性孕妇感染，因此CMV血清阳性率高地区占主要 全球先天性巨细胞病毒负担的一部分。对小鼠和人类的研究表明，CMV具有深刻的 对先天性和适应性免疫系统的影响。然而，对于CMV何时发生， 免疫系统的印记，以及怀孕期间母体CMV感染是否会影响胎儿 即使在没有CMV传播的情况下，也能促进发育和免疫力。在这项资助中，我们的目的是研究 使用生物学相关的恒河猴研究母体暴露于CMV感染对胎儿免疫的影响 HCMV的非人灵长类（NHP）动物模型。我们假设母亲接触CMV感染 在怀孕期间诱导干扰细胞代谢，对免疫细胞群产生不利影响 利用共同的代谢途径，导致（i）迄今尚未认识到的CMV介导的代谢途径的影响， 母胎界面先天免疫和适应性免疫失调，以及（ii）表观遗传修饰 以及对胎儿T和B淋巴细胞、单核细胞和NK细胞的功能影响。我们将利用一个综合的 细胞免疫学检测、转录组学和代谢组学方法研究CMV的作用 感染对NHP模型中胎盘免疫代谢和胎儿免疫的影响。我们的目标是：#1。到 探讨慢性CMV感染对胎盘免疫代谢及胎儿免疫功能的影响; #2。探讨妊娠期实验性原发CMV感染对胎盘的影响， 免疫代谢和胎儿免疫。