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Human Cytomegalovirus miRNAs Regulate TGF-β to Mediate Myelosuppression while Maintaining Viral Latency in CD34+ Hematopoietic Progenitor Cells.
Cell Host & Microbe ( IF 20.6 ) Pub Date : 2019-12-19 , DOI: 10.1016/j.chom.2019.11.013
Meaghan H Hancock 1 , Lindsey B Crawford 1 , Andrew H Pham 1 , Jennifer Mitchell 1 , Hillary M Struthers 1 , Andrew D Yurochko 2 , Patrizia Caposio 1 , Jay A Nelson 1
Affiliation  

Infection with human cytomegalovirus (HCMV) remains a significant cause of morbidity and mortality following hematopoietic stem cell transplant (HSCT) because of various hematologic problems, including myelosuppression. Here, we demonstrate that latently expressed HCMV miR-US5-2 downregulates the transcriptional repressor NGFI-A binding protein (NAB1) to induce myelosuppression of uninfected CD34+ hematopoietic progenitor cells (HPCs) through an increase in TGF-β production. Infection of HPCs with an HCMVΔmiR-US5-2 mutant resulted in decreased TGF-β expression and restoration of myelopoiesis. In contrast, we show that infected HPCs are refractory to TGF-β signaling as another HCMV miRNA, miR-UL22A, downregulates SMAD3, which is required for maintenance of latency. Our data suggest that latently expressed viral miRNAs manipulate stem cell homeostasis by inducing secretion of TGF-β while protecting infected HPCs from TGF-β-mediated effects on viral latency and reactivation. These observations provide a mechanism through which HCMV induces global myelosuppression following HSCT while maintaining lifelong infection in myeloid lineage cells.

中文翻译:

人巨细胞病毒 miRNA 调节 TGF-β 以介导骨髓抑制,同时维持 CD34+ 造血祖细胞中的病毒潜伏期。

由于各种血液学问题,包括骨髓抑制,人类巨细胞病毒 (HCMV) 感染仍然是造血干细胞移植 (HSCT) 后发病率和死亡率的重要原因。在这里,我们证明潜伏表达的 HCMV miR-US5-2 下调转录抑制因子 NGFI-A 结合蛋白 (NAB1),从而通过增加 TGF-β 的产生来诱导未感染的 CD34+ 造血祖细胞 (HPC) 的骨髓抑制。用 HCMVΔmiR-US5-2 突变体感染 HPC 导致 TGF-β 表达降低和骨髓细胞生成恢复。相比之下,我们表明受感染的 HPC 对 TGF-β 信号是难治的,因为另一种 HCMV miRNA,miR-UL22A,下调 SMAD3,这是维持潜伏期所必需的。我们的数据表明,潜伏表达的病毒 miRNA 通过诱导 TGF-β 分泌来操纵干细胞稳态,同时保护受感染的 HPC 免受 TGF-β 介导的病毒潜伏期和再激活影响。这些观察结果提供了一种机制,通过该机制,HCMV 在 HSCT 后诱导整体骨髓抑制,同时维持骨髓谱系细胞的终生感染。
更新日期:2019-12-19
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