Human Cytomegalovirus miRNAs Regulate TGF-β to Mediate Myelosuppression while Maintaining Viral Latency in CD34+ Hematopoietic Progenitor Cells

Meaghan H. Hancock, Lindsey B. Crawford, Andrew H. Pham, Jennifer Mitchell, Hillary M. Struthers, Andrew D. Yurochko, Patrizia Caposio, Jay A. Nelson

Research output: Contribution to journalArticle

5 Scopus citations

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 languageEnglish (US)
Pages (from-to)104-114.e4
JournalCell Host and Microbe
Volume27
Issue number1
DOIs
StatePublished - Jan 8 2020

Keywords

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

ASJC Scopus subject areas

  • Parasitology
  • Microbiology
  • Virology

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