Human cytomegalovirus infection inhibits CXCL12- mediated migration and invasion of human extravillous cytotrophoblasts.
Human cytomegalovirus infection inhibits CXCL12- mediated migration and invasion of human extravillous cytotrophoblasts.
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DOI：
10.1186/1743-422x-9-255
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发表时间：
2012-11-01
期刊：
影响因子：
4.8
通讯作者：
Morris CA
中科院分区：
文献类型：
--
作者：
Warner JA;Zwezdaryk KJ;Day B;Sullivan DE;Pridjian G;Morris CA
在妊娠的前三个月，一系列严格调控的相互作用控制着胎儿来源的绒毛外细胞滋养层细胞（EVT）的高度侵袭性群体的形成。成功妊娠依赖于EVT对子宫壁和母体螺旋动脉的有效侵入。滋养层细胞浸润失调与宫内生长受限、出生缺陷、自然流产和先兆子痫有关。许多可溶性生长因子、细胞因子和趋化因子调节这一过程，微调细胞滋养层侵入的时间和空间方面。特别是，CXCL 12/CXCR 4轴已被证明特异性调节细胞滋养层分化，入侵，并在整个早期妊娠的生存。人巨细胞病毒（HCMV）感染与细胞滋养层浸润途径的分化受损有关，特别是对有丝分裂原（包括表皮生长因子（EGF）和肝细胞生长因子（HGF））的反应失调。在这项研究中，HCMV感染对CXCL 12介导的EVT细胞系SGHPL-4的迁移和侵袭的影响进行了研究。HCMV感染显著降低SGHPL-4细胞CXCL 12的分泌，并诱导趋化因子的显著核周积聚。HCMV感染显著增加了CXCL 12的两种已知受体CXCR 4和CXCR 7的mRNA和总细胞表面表达。在功能上，HCMV感染的SGHPL-4细胞在transwell测定中不能响应于可溶性CXCL 12的梯度而迁移或侵入。总的来说，这些研究表明HCMV损害由CXCL 12诱导的EVT迁移和侵袭。由于HCMV能够通过其他相关信号通路的失调抑制EVT迁移和侵袭，因此病毒可能影响多个信号通路以损害胎盘形成并导致HCMV阳性妊娠中观察到的一些胎盘缺陷。
During the first trimester of pregnancy, a series of tightly regulated interactions govern the formation of a highly invasive population of fetal-derived extravillous cytotrophoblasts (EVT). Successful pregnancy is dependent on efficient invasion of the uterine wall and maternal spiral arteries by EVT. Dysregulated trophoblast invasion is associated with intrauterine growth restriction, birth defects, spontaneous abortion and preeclampsia. A number of soluble growth factors, cytokines, and chemokines modulate this process, fine-tuning the temporal and spatial aspects of cytotrophoblast invasion. In particular, the CXCL12/CXCR4 axis has been shown to specifically modulate cytotrophoblast differentiation, invasion, and survival throughout early pregnancy. Infection with human cytomegalovirus (HCMV) has been associated with impaired differentiation of cytotrophoblasts down the invasive pathway, specifically dysregulating the response to mitogens including epidermal growth factor (EGF) and hepatocyte growth factor (HGF). In this study, the effect of HCMV infection on the CXCL12-mediated migration and invasion of the EVT cell line SGHPL-4 was investigated. Infection with HCMV significantly decreased secretion of CXCL12 by SGHPL-4 cells, and induced a striking perinuclear accumulation of the chemokine. HCMV infection significantly increased mRNA and total cell surface expression of the two known receptors for CXCL12: CXCR4 and CXCR7. Functionally, HCMV-infected SGHPL-4 cells were unable to migrate or invade in response to a gradient of soluble CXCL12 in transwell assays. Collectively, these studies demonstrate that HCMV impairs EVT migration and invasion induced by CXCL12. As HCMV has the ability to inhibit EVT migration and invasion through dysregulation of other relevant signaling pathways, it is likely that the virus affects multiple signaling pathways to impair placentation and contribute to some of the placental defects seen in HCMV-positive pregnancies.