Murine Cytomegalovirus Spreads by Dendritic Cell Recirculation

ABSTRACT Herpesviruses have coevolved with their hosts over hundreds of millions of years and exploit fundamental features of their biology. Cytomegaloviruses (CMVs) colonize blood-borne myeloid cells, and it has been hypothesized that systemic dissemination arises from infected stem cells in bone m...

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Autores principales:	Helen E. Farrell, Kimberley Bruce, Clara Lawler, Martha Oliveira, Rhonda Cardin, Nicholas Davis-Poynter, Philip G. Stevenson
Formato:	article
Lenguaje:	EN
Publicado:	American Society for Microbiology 2017
Materias:	chemokine receptors cytomegalovirus dendritic cells virus-host interactions Microbiology QR1-502
Acceso en línea:	https://doaj.org/article/cc989069964647c2914a504ec5d01fe3
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spelling	oai:doaj.org-article:cc989069964647c2914a504ec5d01fe32021-11-15T15:51:51ZMurine Cytomegalovirus Spreads by Dendritic Cell Recirculation10.1128/mBio.01264-172150-7511https://doaj.org/article/cc989069964647c2914a504ec5d01fe32017-11-01T00:00:00Zhttps://journals.asm.org/doi/10.1128/mBio.01264-17https://doaj.org/toc/2150-7511ABSTRACT Herpesviruses have coevolved with their hosts over hundreds of millions of years and exploit fundamental features of their biology. Cytomegaloviruses (CMVs) colonize blood-borne myeloid cells, and it has been hypothesized that systemic dissemination arises from infected stem cells in bone marrow. However, poor CMV transfer by stem cell transplantation argues against this being the main reservoir. To identify alternative pathways for CMV spread, we tracked murine CMV (MCMV) colonization after mucosal entry. We show that following intranasal MCMV infection, lung CD11c+ dendritic cells (DC) migrated sequentially to lymph nodes (LN), blood, and then salivary glands. Replication-deficient virus followed the same route, and thus, DC infected peripherally traversed LN to enter the blood. Given that DC are thought to die locally following their arrival and integration into LN, recirculation into blood represents a new pathway. We examined host and viral factors that facilitated this LN traverse. We show that MCMV-infected DC exited LN by a distinct route to lymphocytes, entering high endothelial venules and bypassing the efferent lymph. LN exit required CD44 and the viral M33 chemokine receptor, without which infected DC accumulated in LN and systemic spread was greatly reduced. Taken together, our studies provide the first demonstration of virus-driven DC recirculation. As viruses follow host-defined pathways, high endothelial venules may normally allow DC to pass from LN back into blood. IMPORTANCE Human cytomegalovirus (HCMV) causes devastating disease in the unborn fetus and in the immunocompromised. There is no licensed vaccine, and preventive measures are impeded by our poor understanding of early events in host colonization. HCMV and murine CMV (MCMV) both infect blood-borne myeloid cells. HCMV-infected blood cells are thought to derive from infected bone marrow stem cells. However, infected stem cells have not been visualized in vivo nor shown to produce virus ex vivo, and hematopoietic transplants poorly transfer infection. We show that MCMV-infected dendritic cells in the lungs reach the blood via lymph nodes, surprisingly migrating into high endothelial venules. Dissemination did not require viral replication. It depended on the constitutively active viral chemokine receptor M33 and on the host hyaluronan receptor CD44. Thus, viral chemokine receptors are a possible target to limit systemic CMV infections.Helen E. FarrellKimberley BruceClara LawlerMartha OliveiraRhonda CardinNicholas Davis-PoynterPhilip G. StevensonAmerican Society for Microbiologyarticlechemokine receptorscytomegalovirusdendritic cellsvirus-host interactionsMicrobiologyQR1-502ENmBio, Vol 8, Iss 5 (2017)
institution	DOAJ
collection	DOAJ
language	EN
topic	chemokine receptors cytomegalovirus dendritic cells virus-host interactions Microbiology QR1-502
spellingShingle	chemokine receptors cytomegalovirus dendritic cells virus-host interactions Microbiology QR1-502 Helen E. Farrell Kimberley Bruce Clara Lawler Martha Oliveira Rhonda Cardin Nicholas Davis-Poynter Philip G. Stevenson Murine Cytomegalovirus Spreads by Dendritic Cell Recirculation
description	ABSTRACT Herpesviruses have coevolved with their hosts over hundreds of millions of years and exploit fundamental features of their biology. Cytomegaloviruses (CMVs) colonize blood-borne myeloid cells, and it has been hypothesized that systemic dissemination arises from infected stem cells in bone marrow. However, poor CMV transfer by stem cell transplantation argues against this being the main reservoir. To identify alternative pathways for CMV spread, we tracked murine CMV (MCMV) colonization after mucosal entry. We show that following intranasal MCMV infection, lung CD11c+ dendritic cells (DC) migrated sequentially to lymph nodes (LN), blood, and then salivary glands. Replication-deficient virus followed the same route, and thus, DC infected peripherally traversed LN to enter the blood. Given that DC are thought to die locally following their arrival and integration into LN, recirculation into blood represents a new pathway. We examined host and viral factors that facilitated this LN traverse. We show that MCMV-infected DC exited LN by a distinct route to lymphocytes, entering high endothelial venules and bypassing the efferent lymph. LN exit required CD44 and the viral M33 chemokine receptor, without which infected DC accumulated in LN and systemic spread was greatly reduced. Taken together, our studies provide the first demonstration of virus-driven DC recirculation. As viruses follow host-defined pathways, high endothelial venules may normally allow DC to pass from LN back into blood. IMPORTANCE Human cytomegalovirus (HCMV) causes devastating disease in the unborn fetus and in the immunocompromised. There is no licensed vaccine, and preventive measures are impeded by our poor understanding of early events in host colonization. HCMV and murine CMV (MCMV) both infect blood-borne myeloid cells. HCMV-infected blood cells are thought to derive from infected bone marrow stem cells. However, infected stem cells have not been visualized in vivo nor shown to produce virus ex vivo, and hematopoietic transplants poorly transfer infection. We show that MCMV-infected dendritic cells in the lungs reach the blood via lymph nodes, surprisingly migrating into high endothelial venules. Dissemination did not require viral replication. It depended on the constitutively active viral chemokine receptor M33 and on the host hyaluronan receptor CD44. Thus, viral chemokine receptors are a possible target to limit systemic CMV infections.
format	article
author	Helen E. Farrell Kimberley Bruce Clara Lawler Martha Oliveira Rhonda Cardin Nicholas Davis-Poynter Philip G. Stevenson
author_facet	Helen E. Farrell Kimberley Bruce Clara Lawler Martha Oliveira Rhonda Cardin Nicholas Davis-Poynter Philip G. Stevenson
author_sort	Helen E. Farrell
title	Murine Cytomegalovirus Spreads by Dendritic Cell Recirculation
title_short	Murine Cytomegalovirus Spreads by Dendritic Cell Recirculation
title_full	Murine Cytomegalovirus Spreads by Dendritic Cell Recirculation
title_fullStr	Murine Cytomegalovirus Spreads by Dendritic Cell Recirculation
title_full_unstemmed	Murine Cytomegalovirus Spreads by Dendritic Cell Recirculation
title_sort	murine cytomegalovirus spreads by dendritic cell recirculation
publisher	American Society for Microbiology
publishDate	2017
url	https://doaj.org/article/cc989069964647c2914a504ec5d01fe3
work_keys_str_mv	AT helenefarrell murinecytomegalovirusspreadsbydendriticcellrecirculation AT kimberleybruce murinecytomegalovirusspreadsbydendriticcellrecirculation AT claralawler murinecytomegalovirusspreadsbydendriticcellrecirculation AT marthaoliveira murinecytomegalovirusspreadsbydendriticcellrecirculation AT rhondacardin murinecytomegalovirusspreadsbydendriticcellrecirculation AT nicholasdavispoynter murinecytomegalovirusspreadsbydendriticcellrecirculation AT philipgstevenson murinecytomegalovirusspreadsbydendriticcellrecirculation
_version_	1718427366292717568

Murine Cytomegalovirus Spreads by Dendritic Cell Recirculation

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