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Human Cytomegalovirus miRNAs Regulate TGF-β to Mediate Myelosuppression while Maintaining Viral Latency in CD34+ Hematopoietic Progenitor Cells
- Source :
- Cell Host & Microbe. 27:104-114.e4
- Publication Year :
- 2020
- Publisher :
- Elsevier BV, 2020.
-
Abstract
- 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.
- Subjects :
- Human cytomegalovirus
0303 health sciences
Myeloid
CD34
Hematopoietic stem cell
Biology
medicine.disease
Microbiology
03 medical and health sciences
Haematopoiesis
0302 clinical medicine
medicine.anatomical_structure
Virology
microRNA
medicine
Cancer research
Parasitology
Myelopoiesis
Stem cell
030217 neurology & neurosurgery
030304 developmental biology
Subjects
Details
- ISSN :
- 19313128
- Volume :
- 27
- Database :
- OpenAIRE
- Journal :
- Cell Host & Microbe
- Accession number :
- edsair.doi...........4fd62e1e63b8173aaeaf12e73e022238