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.

项目摘要/摘要 巨细胞病毒（CMV）是一种普遍存在的物种特异性的ββ病毒，导致终身持久性 免疫能力宿主中无症状的感染。人CMV（HCMV）是最常见的传染性 先天性感染的原因，每年在美国40,000例出生。在子宫内CMV传输发生 在33-50％的原发感染的怀孕CMV官方女性中；它也发生在非主体之后 怀孕的CMV血清阳性女性感染，因此高CMV血清阳性区域占了主要的解释 先天性CMV全球负担的一部分。对小鼠和人类的研究表明，CMV具有深刻的 对先天和适应性免疫系统的影响。但是，了解何时CMV存在差距 烙印免疫系统以及怀孕期间母体CMV感染是否会影响胎儿 即使没有CMV传播，开发和免疫也是如此。在这笔赠款中，我们的目标是研究效果 使用与生物学相关的恒河猕猴对胎儿免疫感染CMV感染的孕产妇感染感染 HCMV的非人类灵长类动物（NHP）动物模型。我们假设母亲暴露于CMV感染 怀孕期间诱导细胞代谢的扰动，对免疫细胞群体产生不利影响 利用常见的代谢途径，导致（i）迄今无法识别的CMV介导的代谢影响 在母亲界面上对先天和适应性免疫的失调，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细胞的功能作用。我们将利用一个组合 细胞免疫学测定，转录组学和代谢组学研究CMV的影响 NHP模型中胎盘免疫代谢和胎儿免疫的感染。我们的具体目标是：＃1。到 研究慢性母体CMV感染对胎盘免疫代谢和胎儿免疫的影响； 和＃2。确定妊娠期间实验性原发性CMV感染对胎盘的影响 免疫代谢和胎儿免疫。