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Murine Cytomegalovirus Spreads by Dendritic Cell Recirculation

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. Ho...

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Autores principales: Farrell, Helen E., Bruce, Kimberley, Lawler, Clara, Oliveira, Martha, Cardin, Rhonda, Davis-Poynter, Nicholas, Stevenson, Philip G.
Formato: Online Artículo Texto
Lenguaje:English
Publicado: American Society for Microbiology 2017
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5626969/
https://www.ncbi.nlm.nih.gov/pubmed/28974616
http://dx.doi.org/10.1128/mBio.01264-17
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author Farrell, Helen E.
Bruce, Kimberley
Lawler, Clara
Oliveira, Martha
Cardin, Rhonda
Davis-Poynter, Nicholas
Stevenson, Philip G.
author_facet Farrell, Helen E.
Bruce, Kimberley
Lawler, Clara
Oliveira, Martha
Cardin, Rhonda
Davis-Poynter, Nicholas
Stevenson, Philip G.
author_sort Farrell, Helen E.
collection PubMed
description 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.
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spelling pubmed-56269692017-10-04 Murine Cytomegalovirus Spreads by Dendritic Cell Recirculation Farrell, Helen E. Bruce, Kimberley Lawler, Clara Oliveira, Martha Cardin, Rhonda Davis-Poynter, Nicholas Stevenson, Philip G. mBio Research Article 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. American Society for Microbiology 2017-10-03 /pmc/articles/PMC5626969/ /pubmed/28974616 http://dx.doi.org/10.1128/mBio.01264-17 Text en Copyright © 2017 Farrell et al. https://creativecommons.org/licenses/by/4.0/ This is an open-access article distributed under the terms of the Creative Commons Attribution 4.0 International license (https://creativecommons.org/licenses/by/4.0/) .
spellingShingle Research Article
Farrell, Helen E.
Bruce, Kimberley
Lawler, Clara
Oliveira, Martha
Cardin, Rhonda
Davis-Poynter, Nicholas
Stevenson, Philip G.
Murine Cytomegalovirus Spreads by Dendritic Cell Recirculation
title 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_short Murine Cytomegalovirus Spreads by Dendritic Cell Recirculation
title_sort murine cytomegalovirus spreads by dendritic cell recirculation
topic Research Article
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5626969/
https://www.ncbi.nlm.nih.gov/pubmed/28974616
http://dx.doi.org/10.1128/mBio.01264-17
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