Delecluse Susanne, Baccianti Francesco, Zala Manon, Steffens Alina, Drenda Carolin, Judt Daniel, Holland-Letz Tim, Poirey Remy, Sujobert Pierre, Delecluse Henri-Jacques
Unit D400, DKFZ, Heidelberg, Germany.
Inserm joint unit, Heidelberg, Germany.
Nat Commun. 2025 May 19;16(1):4581. doi: 10.1038/s41467-025-59813-z.
Infection with the Epstein-Barr virus (EBV) is a major risk factor for the development of cancer and autoimmune disorders. The virus enters the body in the pharynx, but EBV causes disease in distant organs, including the gut and the brain. Here we show, using in vitro culture and mouse infection models, that EBV-infected B cells display features of homing cells. Infected B cells undergo migration following paracrine CCL4 release and CCR1 induction, while CCR1 deficiency inhibits migration and, unexpectedly, proliferation of infected B cells. Furthermore, migrating EBV-infected B cells undergo CCL4-dependent diapedesis, induce ICAM-1 on endothelial cells, and disrupt the integrity of endothelial barriers. Both migration and diapedesis are regulated by FAK, with FAK inhibition blocking growth and survival of EBV-transformed B cells, as well as their spreading to spleen and brain in an animal model in vivo. Moreover, IL-10 secreted by EBV-infected B cells attracts and facilitates diapedesis of EBV-negative CD52CD11c B cells, which have reported autoimmune properties. Our results thus provide mechanistic insight on EBV-induced B cell dysregulation, and also hint curbing migration as a potential target for reducing the pathogenicity of EBV-infected B cells.
感染爱泼斯坦-巴尔病毒（EBV）是引发癌症和自身免疫性疾病的主要风险因素。该病毒通过咽部进入人体，但EBV会在包括肠道和大脑在内的远处器官引发疾病。在此，我们利用体外培养和小鼠感染模型表明，EBV感染的B细胞表现出归巢细胞的特征。被感染的B细胞在旁分泌CCL4释放和CCR1诱导后发生迁移，而CCR1缺陷会抑制迁移，并且出乎意料的是，还会抑制被感染B细胞的增殖。此外，迁移的EBV感染B细胞会发生CCL4依赖性的穿膜迁移，在内皮细胞上诱导ICAM-1，并破坏内皮屏障的完整性。迁移和穿膜迁移均受黏着斑激酶（FAK）调节，抑制FAK会阻断EBV转化的B细胞的生长和存活，以及它们在体内动物模型中向脾脏和大脑的扩散。此外，EBV感染的B细胞分泌的白细胞介素-10会吸引并促进具有自身免疫特性的EBV阴性CD52CD11c B细胞的穿膜迁移。因此，我们的研究结果为EBV诱导的B细胞失调提供了机制上的见解，也暗示抑制迁移可能是降低EBV感染B细胞致病性的潜在靶点。
