Abstract
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.
Original language | English (US) |
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Pages (from-to) | 104-114.e4 |
Journal | Cell Host and Microbe |
Volume | 27 |
Issue number | 1 |
DOIs | |
State | Published - Jan 8 2020 |
Keywords
- CD34 hematopoietic progenitor cells
- NAB1
- SMAD3
- TGF-β
- hematopoiesis
- human cytomegalovirus
- latency
- miRNAs
- myelosuppression
ASJC Scopus subject areas
- Parasitology
- Microbiology
- Virology