Cell Host & Microbe
Volume 27, Issue 1, 8 January 2020, Pages 104-114.e4
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Article
Human Cytomegalovirus miRNAs Regulate TGF-β to Mediate Myelosuppression while Maintaining Viral Latency in CD34+ Hematopoietic Progenitor Cells

https://doi.org/10.1016/j.chom.2019.11.013Get rights and content
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Highlights

  • Latent HCMV infection of stem cells induces the myelosuppressive cytokine TGF-β

  • HCMV miR-US5-2 targets the transcriptional repressor NAB1 to mediate TGF-β expression

  • HCMV miR-UL22A downregulates SMAD3 to block TGF-β signaling in the infected cell

  • Blocking TGF-β signaling is critical for HCMV latency and genome maintenance

Summary

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.

Keywords

human cytomegalovirus
miRNAs
hematopoiesis
myelosuppression
TGF-β
NAB1
SMAD3
latency
CD34+ hematopoietic progenitor cells

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