Galectin-9 Facilitates Epstein-Barr Virus Latent Infection and Lymphomagenesis in Human B Cells.
Galectin-9 Facilitates Epstein-Barr Virus Latent Infection and Lymphomagenesis in Human B Cells.
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DOI：
10.1128/spectrum.04932-22
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发表时间：
2023-02-14
影响因子：
3.7
通讯作者：
中科院分区：
文献类型：
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免疫调节剂半乳糖凝集素 9 (Gal-9) 通常参与细胞增殖的调节，但根据细胞类型的不同，其影响也不同。在这里，我们发现，从早期感染阶段到成熟淋巴母细胞系（LCL）阶段，Epstein-Barr病毒（EBV）感染的原代B细胞中Gal-9的表达持续增加。这种持续的上调与与细胞增殖相关的基因组的上调平行，例如氧化磷酸化、细胞周期激活和 DNA 复制。敲低或阻断Gal-9表达会阻碍潜伏感染的建立和EBV感染B细胞的生长，而外源Gal-9蛋白则促进EBV急性和潜伏感染以及EBV感染早期B细胞的生长。从机械角度来看，干扰素基因刺激剂 (STING) 激活或信号转导和转录激活剂 3 (STAT3) 抑制阻碍了 EBV 感染的 B 细胞的生长并促进 Gal-9 诱导的类淋巴母细胞系 (LCL) 转化。因此，体外 293T 细胞中强制 EBV 核抗原 1 (EBNA1) 表达可上调 Gal-9 表达。临床数据显示，B 细胞淋巴瘤 (BCL) 中 Gal-9 的表达与 EBNA1 和疾病分期呈正相关。靶向 Gal-9 可减缓异种移植免疫缺陷小鼠中 LCL 肿瘤的生长和转移。这些发现强调了 Gal-9 在 EBV 相关 BCL 中的致癌作用，表明 Gal-9 促进了 EBV 感染的 B 细胞的转化。重要性 Epstein-Barr 病毒 (EBV) 和宿主细胞转录组之间的交互作用在 EBV 相关恶性肿瘤的发生过程中发挥着重要作用。在这里，我们首先观察到，在 EBV 转化的 B 细胞永生化过程中，内源性 Gal-9 表达持续增加，同时抗病毒信号传导发生了翻转的 V 型变化。 Gal-9 的上调促进了 EBV 感染的 B 细胞的生长和潜伏感染，该细胞通过抑制 STING 信号传导并随后促进 STAT3 磷酸化与 B 细胞来源的肿瘤相关。 EBV核抗原EBNA1诱导Gal-9表达，并在EBV感染的B细胞中与Gal-9形成正反馈环。 B 细胞淋巴瘤 (BCL) 患者的肿瘤 Gal-9 水平与疾病分期和 EBNA1 表达呈正相关。靶向 Gal-9 可以减缓免疫缺陷小鼠 LCL 肿瘤的生长和转移。总而言之，我们的研究结果表明 Gal-9 通过与 EBNA1 和 STING 信号的交互作用参与 EBV 阳性 BCL 的淋巴瘤发生。
The immune regulator galectin-9 (Gal-9) is commonly involved in the regulation of cell proliferation, but with various impacts depending on the cell type. Here, we revealed that Gal-9 expression was persistently increased in Epstein-Barr virus (EBV)-infected primary B cells from the stage of early infection to the stage of mature lymphoblastoid cell lines (LCLs). This sustained upregulation paralleled that of gene sets related to cell proliferation, such as oxidative phosphorylation, cell cycle activation, and DNA replication. Knocking down or blocking Gal-9 expression obstructed the establishment of latent infection and outgrowth of EBV-infected B cells, while exogenous Gal-9 protein promoted EBV acute and latent infection and outgrowth of EBV-infected B cells at the early infection stage. Mechanically, stimulator of interferon gene (STING) activation or signal transducer and activator of transcription 3 (STAT3) inhibition impeded the outgrowth of EBV-infected B cells and promotion of Gal-9-induced lymphoblastoid cell line (LCL) transformation. Accordingly, Gal-9 expression was upregulated by forced EBV nuclear antigen 1 (EBNA1) expression in 293T cells in vitro. Clinical data showed that Gal-9 expression in B-cell lymphomas (BCLs) correlated positively with EBNA1 and disease stage. Targeting Gal-9 slowed LCL tumor growth and metastasis in xenografted immunodeficient mice. These findings highlight an oncogenic role of Gal-9 in EBV-associated BCLs, indicating that Gal-9 boosts the transformation of EBV-infected B cells. IMPORTANCE The cross talk between Epstein-Barr virus (EBV) and the host cell transcriptome assumes important roles in the oncogenesis of EBV-associated malignancies. Here, we first observed that endogenous Gal-9 expression was persistently increased along with an overturned V-type change in antivirus signaling during the immortalization of EBV-transformed B cells. Upregulation of Gal-9 promoted the outgrowth and latent infection of EBV-infected B cells, which was linked to B-cell-origin tumors by suppressing STING signaling and subsequently promoting STAT3 phosphorylation. EBV nuclear antigen EBNA1 induced Gal-9 expression and formed a positive feedback loop with Gal-9 in EBV-infected B cells. Tumor Gal-9 levels were positively correlated with disease stage and EBNA1 expression in patients with B-cell lymphomas (BCLs). Targeting Gal-9 slowed the growth and metastases of LCL tumors in immunodeficient mice. Altogether, our findings indicate that Gal-9 is involved in the lymphomagenesis of EBV-positive BCLs through cross talk with EBNA1 and STING signals.
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影响因子：
16.6
作者：
Giovannone N;Liang J;Antonopoulos A;Geddes Sweeney J;King SL;Pochebit SM;Bhattacharyya N;Lee GS;Dell A;Widlund HR;Haslam SM;Dimitroff CJ
通讯作者：
Dimitroff CJ
影响因子：
10.1
作者：
Garcia-Reyero J;Martinez Magunacelaya N;Gonzalez de Villambrosia S;Loghavi S;Gomez Mediavilla A;Tonda R;Beltran S;Gut M;Pereña Gonzalez A;d'Ámore E;Visco C;Khoury JD;Montes-Moreno S
通讯作者：
Montes-Moreno S
影响因子：
3
作者：
Hirashima, M;Kashio, Y;Nakamura, T
通讯作者：
Nakamura, T
DOI：
10.1182/asheducation-2005.1.231
发表时间：
2005-01-01
期刊：
Hematology. American Society of Hematology. Education Program
影响因子：
--
作者：
Poppema, Sibrand
通讯作者：
Poppema, Sibrand
影响因子：
64.8
作者：
通讯作者：
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