CMV infection impact 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β疱疹病毒，可导致终生持续。 在具有免疫能力的宿主中的无症状感染。人类巨细胞病毒(HCMV)是最常见的传染性病毒 先天感染的原因，每年在美国有40,000名新生儿并发。巨细胞病毒在宫内传播 在33%-50%的CMV血清阴性的妊娠妇女中，原发感染也发生在非原发感染之后 妊娠巨细胞病毒血清阳性妇女的感染，因此巨细胞病毒血清阳性率高的区域是主要原因 先天性巨细胞病毒是全球负担的一部分。对小鼠和人类的研究表明，CMV具有深远的 对先天性免疫系统和获得性免疫系统的影响。然而，关于CMV何时出现的知识存在差距。 母体在孕期感染巨细胞病毒是否会影响胎儿免疫系统 发育和免疫，即使在没有CMV传播的情况下也是如此。在这笔赠款中，我们的目的是研究 母体暴露于巨细胞病毒感染对胎儿免疫功能的影响 人巨细胞病毒非人灵长类动物模型。我们假设母亲接触到巨细胞病毒感染 怀孕期间会引起细胞代谢紊乱，从而对免疫细胞群产生不利影响 利用共同的代谢途径，导致(I)CMV介导的代谢的影响迄今不为人知 母胎交界处先天免疫和获得性免疫的失调，以及(Ii)表观遗传修饰 对胎儿T、B淋巴细胞、单核细胞和NK细胞的功能影响。我们将利用合并后的 细胞免疫学、转录组学和代谢组学方法研究巨细胞病毒的作用 NHP模型对胎盘免疫代谢和胎儿免疫的影响我们的具体目标是：#1. 探讨母体慢性巨细胞病毒感染对胎盘免疫代谢和胎儿免疫功能的影响； 2.确定妊娠期实验性原发巨细胞病毒感染对胎盘的影响 免疫代谢与胎儿免疫。

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.