Cytomegalovirus Infection Triggers the Secretion of the PPARγ Agonists 15-Hydroxyeicosatetraenoic Acid (15-HETE) and 13-Hydroxyoctadecadienoic Acid (13-HODE) in Human Cytotrophoblasts and Placental Cultures.
Cytomegalovirus Infection Triggers the Secretion of the PPARγ Agonists 15-Hydroxyeicosatetraenoic Acid (15-HETE) and 13-Hydroxyoctadecadienoic Acid (13-HODE) in Human Cytotrophoblasts and Placental Cultures.
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DOI：
10.1371/journal.pone.0132627
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发表时间：
2015
期刊：
影响因子：
3.7
通讯作者：
Chavanas S
中科院分区：
文献类型：
--
作者：
Leghmar K;Cenac N;Rolland M;Martin H;Rauwel B;Bertrand-Michel J;Le Faouder P;Bénard M;Casper C;Davrinche C;Fournier T;Chavanas S
人巨细胞病毒（HCMV）的先天性感染是中枢神经系统先天性异常的主要原因。HCMV引起的胎盘感染可使病毒传播至胎儿，并可能导致宫内生长受限、先兆子痫样症状或流产。我们以前报道过HCMV激活过氧化物酶体增殖物激活受体γ（PPARγ）在细胞滋养层细胞中进行自身复制。在这里，我们研究了感染的细胞滋养层细胞中PPARγ激活的分子基础。我们发现，在感染的HIPEC细胞滋养层细胞中，由HCMV颗粒携带的cPLA 2是有效激活PPARγ所必需的，并抑制细胞迁移。天然的PPARγ激动剂由PLA 2驱动的亚油酸和花生四烯酸的氧化产生。因此，使用HPLC结合质谱法，我们公开了在感染后6小时，HIPEC细胞滋养层中和从HIPEC细胞滋养层中的13-羟基十八碳二烯酸（13-HODE）和15-羟基二十碳四烯酸（15-HETE）的细胞和分泌水平显著增加。13-HODE治疗未感染的HIPEC，重现了感染的影响（PPARγ活化，迁移障碍）。我们发现，感染正常的第一个任期的人胎盘组织培养物，导致分泌的15-HETE和13-HODE水平显着增加。本研究结果提示15-HETE和13-HODE可能是HCMV先天性感染的新的致病效应物，为HCMV先天性感染的发病机制提供了新的认识。
Congenital infection by human cytomegalovirus (HCMV) is a leading cause of congenital abnormalities of the central nervous system. Placenta infection by HCMV allows for viral spread to fetus and may result in intrauterine growth restriction, preeclampsia-like symptoms, or miscarriages. We previously reported that HCMV activates peroxisome proliferator-activated receptor gamma (PPARγ) for its own replication in cytotrophoblasts. Here, we investigated the molecular bases of PPARγ activation in infected cytotrophoblasts. We show that onboarded cPLA2 carried by HCMV particles is required for effective PPARγ activation in infected HIPEC cytotrophoblasts, and for the resulting inhibition of cell migration. Natural PPARγ agonists are generated by PLA2 driven oxidization of linoleic and arachidonic acids. Therefore, using HPLC coupled with mass spectrometry, we disclosed that cellular and secreted levels of 13-hydroxyoctadecadienoic acid (13-HODE) and 15-hydroxyeicosatetraenoic acid (15-HETE) were significantly increased in and from HIPEC cytotrophoblasts at soon as 6 hours post infection. 13-HODE treatment of uninfected HIPEC recapitulated the effect of infection (PPARγ activation, migration impairment). We found that infection of histocultures of normal, first-term, human placental explants resulted in significantly increased levels of secreted 15-HETE and 13-HODE. Our findings reveal that 15-HETE and 13-HODE could be new pathogenic effectors of HCMV congenital infection They provide a new insight about the pathogenesis of congenital infection by HCMV.