Human Cytomegalovirus Encodes a Novel FLT3 Receptor Ligand Necessary for Hematopoietic Cell Differentiation and Viral Reactivation

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 Fms-like 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.

Human Cytomegalovirus Infection Suppresses CD34+ Progenitor Cell Engraftment in Humanized Mice

“…This new HCMV-huBLT mouse model provides an ideal system to examine the effects of different viral genes on hematopoiesis that are generally too complex for tissue culture-based systems and impossible to experimentally approach in human patients. We recently published that both HCMV UL7 and US28 are required for the expansion of the CD14 + monocyte population in the huNSG model [26,27]. This novel model system will provide a tractable in vivo system in which to determine the effect of these and other viral genes during HSCT.…”

Cell signaling and cytomegalovirus reactivation: what do Src family kinases have to do with it?

“…Interestingly, the identification of a role for SFK activity during HCMV reactivation became more intriguing in light of emerging data arguing that the virus itself was not a passive observer in the process of latency and reactivation. Very recently it has been shown that an HCMV gene product, UL7, binds to flt3 ligand receptor to drive myelopoiesis and HCMV reactivation [54]. An important component of flt3 ligand signaling is the activation of SFKs [55] which may suggest a more involved role for SFKs in viral reactivation above the recruitment of MOZ to the MIEP.…”

Human Cytomegalovirus Infection Suppresses CD34+ Progenitor Cell Engraftment in Humanized Mice

“…This new HCMV-huBLT mouse model provides an ideal system to examine the effects of different viral genes on hematopoiesis that are generally too complex for tissue culture based systems and impossible to experimentally approach in human patients. We recently published that both HCMV UL7 and US28 are required for the expansion of the CD14 + monocyte population in the huNSG model [21,22]. This novel model system will provide a tractable in vivo system in which to determine the effect of these and other viral genes during HSCT.…”