Human cytomegalovirus encodes a novel FLT3 receptor ligand necessary for hematopoietic cell differentiation and viral reactivation

Lindsey B. Crawford, Jung Heon Kim, Donna Collins-McMillen, Byeong Jae Lee, Igor Landais, Christine Held, Jay Nelson, Andrew D. Yurochko, Patrizia Caposio

Research output: Contribution to journalArticle

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Abstract

The ability of human cytomegalovirus (HCMV) to reactivate from latent infection of hematopoietic progenitor cells (HPCs) is intimately linked to cellular differentiation. HCMV encodes UL7 that our group has shown is secreted from infected cells and induces angiogenesis. In this study, we show that UL7 is a ligand for Fmslike tyrosine kinase 3 receptor (Flt-3R), a well-known critical factor in HPC differentiation. We observed that UL7 directly binds Flt-3R and induces downstream signaling cascades, including phosphatidylinositol 3-kinase (PI3K)/Akt and mitogen-activated protein kinase (MAPK)/extracellular signal-regulated kinase (ERK) pathways. Importantly, we show that UL7 protein induces differentiation of both CD34+ HPCs and CD14+ monocytes. Last, we show that an HCMV mutant lacking UL7 fails to reactivate in CD34+ HPCs in vitro as well as in humanized mice. These observations define the first virally encoded differentiation factor with significant implications not only for HCMV reactivation but also for alteration of the hematopoietic compartment in transplant patients. IMPORTANCE Human cytomegalovirus (HCMV) remains a significant cause of morbidity and mortality in allogeneic hematopoietic stem cell transplant recipients. CD34+ hematopoietic progenitor cells (HPCs) represent a critical reservoir of latent HCMV in the transplant population, thereby providing a source of virus for dissemination to visceral organs. HCMV reactivation has been linked to HPC/myeloid cellular differentiation; however, the mechanisms involved in these events are poorly understood at the molecular level. In this study, we show that a viral protein is a ligand for Fms-like tyrosine kinase 3 receptor (Flt-3R) and that the binding of HCMV UL7 to the Flt-3R triggers HPC and monocyte differentiation. Moreover, the loss of UL7 prevents viral reactivation in HPCs in vitro as well as in humanized mice. These observations define the first virally encoded differentiation factor with significant implications not only for HCMV reactivation but also for alteration of the hematopoietic compartment in transplant patients.

Original languageEnglish (US)
Article numbere00682-18
JournalmBio
Volume9
Issue number2
DOIs
StatePublished - Mar 1 2018

Fingerprint

Hematopoietic Stem Cells
Cytomegalovirus
Cell Differentiation
Ligands
Receptor Protein-Tyrosine Kinases
Transplants
Monocytes
Phosphatidylinositol 3-Kinase
Vascular Endothelial Growth Factor Receptor-1
Extracellular Signal-Regulated MAP Kinases
Viral Proteins
Mitogen-Activated Protein Kinases
Viruses
Morbidity
Mortality
Infection

Keywords

  • Flt3 receptor
  • Hematopoiesis
  • Human cytomegalovirus
  • PUL7
  • Viral reactivation

ASJC Scopus subject areas

  • Microbiology
  • Virology

Cite this

Human cytomegalovirus encodes a novel FLT3 receptor ligand necessary for hematopoietic cell differentiation and viral reactivation. / Crawford, Lindsey B.; Kim, Jung Heon; Collins-McMillen, Donna; Lee, Byeong Jae; Landais, Igor; Held, Christine; Nelson, Jay; Yurochko, Andrew D.; Caposio, Patrizia.

In: mBio, Vol. 9, No. 2, e00682-18, 01.03.2018.

Research output: Contribution to journalArticle

Crawford, Lindsey B. ; Kim, Jung Heon ; Collins-McMillen, Donna ; Lee, Byeong Jae ; Landais, Igor ; Held, Christine ; Nelson, Jay ; Yurochko, Andrew D. ; Caposio, Patrizia. / Human cytomegalovirus encodes a novel FLT3 receptor ligand necessary for hematopoietic cell differentiation and viral reactivation. In: mBio. 2018 ; Vol. 9, No. 2.
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AU - Landais, Igor

AU - Held, Christine

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