EphA2 is a functional entry receptor for HCMV infection of glioblastoma cells.
EphA2 is a functional entry receptor for HCMV infection of glioblastoma cells.
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EPHA2是用于HCMV感染胶质母细胞瘤细胞的功能入口受体。
DOI：
10.1371/journal.ppat.1011304
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发表时间：
2023-05
期刊：
影响因子：
6.7
通讯作者：
中科院分区：
文献类型：
--
作者：
人巨细胞病毒(HCMV)感染与人脑胶质母细胞瘤有关，但其潜在的感染机制尚未完全阐明。在这里，我们发现EphA2在胶质母细胞瘤中表达上调，并与患者的不良预后相关。EphA2的沉默抑制了人巨细胞病毒的感染，而过表达则促进了人巨细胞病毒的感染，从而使EphA2成为人巨细胞病毒感染胶质母细胞瘤细胞的关键细胞因子。在机制上，EphA2与HCMV Gh/Gl复合体结合，介导膜融合。重要的是，针对EphA2的抑制剂或抗体可抑制胶质母细胞瘤细胞中的HCMV感染。此外，在EphA2抑制剂的作用下，人巨细胞病毒感染在最佳胶质母细胞瘤中也受到抑制。综上所述，我们认为EphA2是胶质母细胞瘤细胞中HCMV感染的关键细胞因子，也是一个潜在的干预靶点。人巨细胞病毒属于β-人疱疹病毒属，是一种普遍存在的引起先天性感染的病原体，与免疫功能低下的移植患者的发病率和死亡率有关。此外，HCMV已被证明可以促进胶质母细胞瘤的进展，胶质母细胞瘤是最常见和最具侵袭性的原发脑瘤。许多研究强调了人巨细胞病毒与胶质母细胞瘤之间的必然关系。但人巨细胞病毒感染胶质母细胞瘤细胞的机制尚未完全阐明。我们发现EphA2是受体酪氨酸激酶(RTKs)家族的成员，在胶质母细胞瘤细胞的HCMV感染过程中起着至关重要的作用。我们的研究表明，EphA2通过与显示在HCMV病毒粒子表面的糖蛋白Gh/Gl/Go相互作用来介导HCMV的感染。我们发现抗EphA2抗体和2，5-二甲基吡咯基苯甲酸衍生物可以阻断人巨细胞病毒在胶质母细胞瘤细胞中的感染，而2，5-二甲基吡咯基苯甲酸衍生物可以剂量依赖的方式阻断人巨细胞病毒在GBOS中的感染，表明开发针对EphA2的抗巨细胞病毒药物的策略是可行的。我们的发现可能有助于未来的研究，努力更好地了解HCMV是如何感染胶质母细胞瘤细胞的，并为创新的抗病毒策略寻找潜在的新靶点。
Human cytomegalovirus (HCMV) infection is associated with human glioblastoma, the most common and aggressive primary brain tumor, but the underlying infection mechanism has not been fully demonstrated. Here, we show that EphA2 was upregulated in glioblastoma and correlated with the poor prognosis of the patients. EphA2 silencing inhibits, whereas overexpression promotes HCMV infection, establishing EphA2 as a crucial cell factor for HCMV infection of glioblastoma cells. Mechanistically, EphA2 binds to HCMV gH/gL complex to mediate membrane fusion. Importantly, the HCMV infection was inhibited by the treatment of inhibitor or antibody targeting EphA2 in glioblastoma cells. Furthermore, HCMV infection was also impaired in optimal glioblastoma organoids by EphA2 inhibitor. Taken together, we propose EphA2 as a crucial cell factor for HCMV infection in glioblastoma cells and a potential target for intervention. Human cytomegalovirus (HCMV) belonged to β-human herpesvirus is a ubiquitous pathogen causing congenital infection and relating to morbidity and mortality in immunocompromised transplant patients. Moreover, HCMV has been demonstrated to promote the progression of glioblastoma, the most common and aggressive primary brain tumor. Many studies highlighted the inevitable relationship between HCMV and glioblastoma. But the underlying mechanism of HCMV infection of glioblastoma cells has not been fully demonstrated. Here we found that EphA2, a member of receptor tyrosine kinases (RTKs) family, played a crucial role in HCMV infection of glioblastoma cells. Our research suggests that EphA2 mediates the infection of HCMV by interacting with glycoproteins gH/gL/gO displaying on the surface of HCMV virion. We find that anti-EphA2 antibody and 2,5-dimethylpyrrolyl benzoic acid derivatives can block HCMV infection in glioblastoma cells, while 2,5-dimethylpyrrolyl benzoic acid derivatives can block HCMV infection in GBOs in a dose-dependent manner, indicating that the strategy of developing an anti-HCMV drug targeting EphA2 is feasible. Our findings may assist future studies striving for a better understanding of how HCMV infects glioblastoma cells and for potential new targets of innovative antiviral strategies.
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DOI：
10.1073/pnas.1119592109
发表时间：
2012-05-08
影响因子：
11.1
作者：
Chakraborty, Sayan;Veettil, Mohanan Valiya;Chandran, Bala
通讯作者：
Chandran, Bala
影响因子：
50.3
作者：
Binda E;Visioli A;Giani F;Lamorte G;Copetti M;Pitter KL;Huse JT;Cajola L;Zanetti N;DiMeco F;De Filippis L;Mangiola A;Maira G;Anile C;De Bonis P;Reynolds BA;Pasquale EB;Vescovi AL
通讯作者：
Vescovi AL
影响因子：
5.4
作者：
Chen, Jia;Schaller, Samantha;Longnecker, Richard
通讯作者：
Longnecker, Richard
影响因子：
4.8
作者：
Liu, Che;Clark, Paul A.;Kalejta, Robert F.
通讯作者：
Kalejta, Robert F.
影响因子：
28.3
作者：
Kabanova A;Marcandalli J;Zhou T;Bianchi S;Baxa U;Tsybovsky Y;Lilleri D;Silacci-Fregni C;Foglierini M;Fernandez-Rodriguez BM;Druz A;Zhang B;Geiger R;Pagani M;Sallusto F;Kwong PD;Corti D;Lanzavecchia A;Perez L
通讯作者：
Perez L