Human Cytomegalovirus-Induced Inhibition of Cytotrophoblast Invasion

人巨细胞病毒诱导的细胞滋养层侵袭抑制

• 批准号: 7614343
• 负责人: CINDY Anne MORRIS
• 金额: $ 29.97万
• 依托单位: TULANE UNIVERSITY OF LOUISIANA
• 依托单位国家: 美国
• 财政年份: 2008
• 资助国家: 美国
• 起止时间: 2008-04-15 至 2013-04-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7614343
• 关键词: 3-Dimensional; Affect; Bioreactors; Cell Line; Cells; Communities; Cytomegalovirus; Cytomegalovirus Infections; Data; Embryo; Environment; Event; Exhibits; Experimental Designs; Fetal Growth Retardation; Fetus; Fibrin; First Pregnancy Trimester; Gelatinase A; Gelatinase B; Gene Expression; Glycoproteins; Goals; Growth Factor; Herpesviridae; Human Herpesvirus 4; Hypoxia; Immediate-Early Genes; Immediate-Early Proteins; Infection; Interleukin-10; Interstitial Collagenase; Invaded; Kinetics; Lytic; Maternal-Fetal Exchange; Matrix Metalloproteinase Inhibitor; Matrix Metalloproteinases; Mediating; Metalloproteases; Modeling; Molecular; Morbidity - disease rate; Myometrial; Oxygen; Partial Pressure; Pathology; Phenotype; Placenta; Placentation; Plasminogen Activator Inhibitor 1; Pre-Eclampsia; Pregnancy; Pregnancy loss; Pregnant Uterus; Premature Birth; Premature Labor; Proteins; Research Personnel; Side; Signal Transduction; Site; Spiral Artery of the Endometrium; Staging; Stromelysin 1; System; Technology; Testing; Tissue Engineering; Tissues; Transforming Growth Factors; Up-Regulation; Viral; Viral Genes; Viral Proteins; Virion; Woman; congenital infection; cytokine; cytotrophoblast; fetal; implantation; in vitro Model; in vivo Model; inhibitor/antagonist; interstitial; lytic replication; migration; mortality; novel; planetary Atmosphere; protein expression; public health relevance; reactivation from latency; reproductive; therapeutic target; trophoblast

DESCRIPTION (provided by applicant): Significant morbidity and mortality is associated with symptomatic congenital infection with the herpes virus human cytomegalovirus (HCMV). Fifteen percent of women with primary HCMV infection spontaneously abort during early pregnancy; and it is the placenta, not the embryo or fetus that shows evidence of infection. Pathological consequences of placental HCMV infection, including first trimester pregnancy loss, intrauterine growth restriction, pre-eclampsia and preterm labor, are believed to be mediated by the inability of extravillous cytotrophoblasts (EVT) to adequately invade the uterine wall during early first trimester pregnancy resulting in impaired remodeling of maternal spiral arteries and shallow placentation. Preliminary studies demonstrate that HCMV infection of first trimester EVT results in inhibition of EVT invasion and in significant reduction of expression and activity of invasion-promoting matrix metalloproteinase (MMP)-2 and MMP-9. HCMV-induced inhibition of EVT occurs along with increased expression of transforming growth factor (TGF)-21, a factor known to inhibit EVT invasion. Since EVT invasion occurs during first trimester pregnancy when the fetal side of the placental environment is relatively hypoxic and since hypoxia, in other systems, is capable of activating herpesvirus gene expression and lytic replication, low oxygen partial pressure during placentation may actually augment the ability of HCMV to inhibit EVT invasion. To determine the molecular mechanism(s) by which HCMV inhibits EVT invasion, which is the broad, long-term objective of the studies proposed herein, a novel, biologically relevant model of EVT invasion has been developed using bioreactor tissue engineering technology. The hypotheses of the studies proposed are that that HCMV, and more specifically, the viral envelope glycoprotein B (gB) and/or immediate- early gene products, IE1-72 and IE2-86, inhibit EVT invasion during placentation through activation of TGF-21 and modulation of MMP activity; and further, that hypoxia increases the ability of HCMV to inhibit EVT invasion through upregulation of HCMV IE expression and lytic replication. The Specific Aims to test these hypotheses are (1) to determine whether the inhibition of invasion of cultured EVT by HCMV is mediated by early events in the HCMV replication cycle (2) to determine whether HCMV represses invasion- promoting MMP-2, MMP-3, MMP-9 and uPA, and upregulates invasion-repressing TIMP-1, TIMP-2 and PAI-1 in cultured EVT and whether HCMV inhibits the invasiveness of cultured EVT through activation of TGF-21 and (3) to determine whether the relatively hypoxic atmosphere encountered by differentiating CTB during first trimester pregnancy enhances HCMV-induced inhibition of interstitial and endovascular invasion by EVT through increased lytic HCMV replication. Elucidating mechanisms by which HCMV impairs placentation may be key to understanding fetal and maternal pathologies associated with intrauterine HCMV infection. PUBLIC HEALTH RELEVANCE: Fifteen percent of women with primary human cytomegalovirus (HCMV) infection spontaneously abort during early pregnancy, and it is the placenta, not the embryo or fetus, that shows evidence of infection. Additionally, HCMV infection may cause premature delivery, intrauterine growth restriction or pre-eclampsia, all of which are associated with placental pathology. These complications are believed to be, at least in part, the result of inadequate extravillous cytotrophoblast invasion (EVT) of the uterine wall and impaired remodeling of the maternal spiral arteries during early stages of placental development. Defining how HCMV impairs EVT invasion is of major importance to the reproductive community and may provide additional therapeutic targets to maintain viable pregnancy.

描述（由申请人提供）：显着的发病率和死亡率与疱疹病毒人类巨细胞病毒（HCMV）的症状先天性感染有关。原发性HCMV感染的妇女中有15％在怀孕初期自发流产；显示感染的证据是胎盘，而不是胚胎或胎儿。据信，胎盘HCMV感染的病理后果，包括妊娠妊娠丧失，宫内生长限制，前球和早产，被认为是由于在第一十一中妊娠的早期临时造成的临床造成的临床造成的临时，是由于无法充分的子宫造成的胎儿造成的，是由于无法充分地侵入子宫内的胎儿造成的胎儿的临床改造而介导的。初步研究表明，HCMV感染头三个月EVT导致抑制EVT侵袭，并显着降低了促进侵袭性基质金属蛋白酶（MMP）-2和MMP-9的表达和活性。 HCMV诱导的EVT抑制作用以及转化生长因子（TGF）-21的表达增加，这是已知的抑制EVT侵袭的因子。由于EVT侵袭发生在妊娠孕期期间，当时胎盘环境的胎儿侧相对低氧，并且由于在其他系统中缺氧能够激活疱疹病毒基因表达和裂解复制，因此胎盘递减过程中的低氧部分压力实际上可能会增强HCMV抑制EVT Invision的能力。为了确定HCMV抑制EVT侵袭的分子机制，这是本文提出的研究的广泛，长期目标，使用生物反应器组织工程技术开发了一种新型的EVT侵袭模型。提出的研究的假设是，HCMV，更具体地说，病毒包膜糖蛋白B（GB）和/或立即的早期基因产物IE1-72和IE2-86，通过激活TGF-21的激活和MMP活性的调节，抑制了EVT侵袭。此外，这种缺氧通过上调HCMV IE表达和裂解复制来提高HCMV抑制EVT侵袭的能力。测试这些假设的具体目的是（1）确定HCMV对培养EVT的抑制作用是由HCMV复制周期（2）中的早期事件介导的HCMV是否通过激活TGF-21和（3）抑制了培养的EVT的侵入性，以确定是否通过在三个月妊娠期间与CTB区分CTB遇到的相对低氧大气增强了HCMV诱导的抑制抑制了通过Lytic HCMV复兴的EVT抑制间隙和内膜内的抑制。阐明HCMV损害胎盘的机制可能是了解与宫内HCMV感染相关的胎儿和母体病理的关键。 公共卫生相关性：15％的人类巨细胞病毒（HCMV）感染在怀孕初期自发流产，而胎盘，而不是胚胎或胎儿，这表明了感染的证据。此外，HCMV感染可能导致过早递送，宫内生长限制或先兆子痫，所有这些都与胎盘病理学有关。人们认为，这些并发症至少部分是由于子宫壁不足的子宫内细胞细胞侵袭（EVT）的结果，并且在胎盘发育的早期阶段对母体螺旋动脉的重塑受损。定义HCMV如何损害EVT入侵对生殖社区至关重要，并可能提供额外的治疗靶标以维持可行的妊娠。