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 sh...

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Autores principales:	Lindsey B. Crawford, Jung Heon Kim, Donna Collins-McMillen, Byeong-Jae Lee, Igor Landais, Christine Held, Jay A. Nelson, Andrew D. Yurochko, Patrizia Caposio
Formato:	article
Lenguaje:	EN
Publicado:	American Society for Microbiology 2018
Materias:	Flt3 receptor human cytomegalovirus hematopoiesis pUL7 viral reactivation Microbiology QR1-502
Acceso en línea:	https://doaj.org/article/e112ec564a7b40c191ff06dc9080fbc1
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spelling	oai:doaj.org-article:e112ec564a7b40c191ff06dc9080fbc12021-11-15T15:53:26ZHuman Cytomegalovirus Encodes a Novel FLT3 Receptor Ligand Necessary for Hematopoietic Cell Differentiation and Viral Reactivation10.1128/mBio.00682-182150-7511https://doaj.org/article/e112ec564a7b40c191ff06dc9080fbc12018-05-01T00:00:00Zhttps://journals.asm.org/doi/10.1128/mBio.00682-18https://doaj.org/toc/2150-7511ABSTRACT 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. 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.Lindsey B. CrawfordJung Heon KimDonna Collins-McMillenByeong-Jae LeeIgor LandaisChristine HeldJay A. NelsonAndrew D. YurochkoPatrizia CaposioAmerican Society for MicrobiologyarticleFlt3 receptorhuman cytomegalovirushematopoiesispUL7viral reactivationMicrobiologyQR1-502ENmBio, Vol 9, Iss 2 (2018)
institution	DOAJ
collection	DOAJ
language	EN
topic	Flt3 receptor human cytomegalovirus hematopoiesis pUL7 viral reactivation Microbiology QR1-502
spellingShingle	Flt3 receptor human cytomegalovirus hematopoiesis pUL7 viral reactivation Microbiology QR1-502 Lindsey B. Crawford Jung Heon Kim Donna Collins-McMillen Byeong-Jae Lee Igor Landais Christine Held Jay A. Nelson Andrew D. Yurochko Patrizia Caposio Human Cytomegalovirus Encodes a Novel FLT3 Receptor Ligand Necessary for Hematopoietic Cell Differentiation and Viral Reactivation
description	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. 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.
format	article
author	Lindsey B. Crawford Jung Heon Kim Donna Collins-McMillen Byeong-Jae Lee Igor Landais Christine Held Jay A. Nelson Andrew D. Yurochko Patrizia Caposio
author_facet	Lindsey B. Crawford Jung Heon Kim Donna Collins-McMillen Byeong-Jae Lee Igor Landais Christine Held Jay A. Nelson Andrew D. Yurochko Patrizia Caposio
author_sort	Lindsey B. Crawford
title	Human Cytomegalovirus Encodes a Novel FLT3 Receptor Ligand Necessary for Hematopoietic Cell Differentiation and Viral Reactivation
title_short	Human Cytomegalovirus Encodes a Novel FLT3 Receptor Ligand Necessary for Hematopoietic Cell Differentiation and Viral Reactivation
title_full	Human Cytomegalovirus Encodes a Novel FLT3 Receptor Ligand Necessary for Hematopoietic Cell Differentiation and Viral Reactivation
title_fullStr	Human Cytomegalovirus Encodes a Novel FLT3 Receptor Ligand Necessary for Hematopoietic Cell Differentiation and Viral Reactivation
title_full_unstemmed	Human Cytomegalovirus Encodes a Novel FLT3 Receptor Ligand Necessary for Hematopoietic Cell Differentiation and Viral Reactivation
title_sort	human cytomegalovirus encodes a novel flt3 receptor ligand necessary for hematopoietic cell differentiation and viral reactivation
publisher	American Society for Microbiology
publishDate	2018
url	https://doaj.org/article/e112ec564a7b40c191ff06dc9080fbc1
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Human Cytomegalovirus Encodes a Novel FLT3 Receptor Ligand Necessary for Hematopoietic Cell Differentiation and Viral Reactivation

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