The Role of Transforming Growth Factor β in Cell-to-Cell Contact-Mediated Epstein-Barr Virus Transmission
Infection of Epstein–Barr virus (EBV), a ubiquitous human gamma herpesvirus, is closely linked to various lymphoid and epithelial malignancies. Previous studies demonstrated that the efficiency of EBV infection in epithelial cells is significantly enhanced by coculturing them with latently infected...
Main Authors: | , , , |
---|---|
Format: | Article |
Language: | English |
Published: |
Frontiers Media S.A.
2018-05-01
|
Series: | Frontiers in Microbiology |
Subjects: | |
Online Access: | http://journal.frontiersin.org/article/10.3389/fmicb.2018.00984/full |
id |
doaj-103358b6c3584030930463e94eab09e0 |
---|---|
record_format |
Article |
spelling |
doaj-103358b6c3584030930463e94eab09e02020-11-24T21:57:24ZengFrontiers Media S.A.Frontiers in Microbiology1664-302X2018-05-01910.3389/fmicb.2018.00984343148The Role of Transforming Growth Factor β in Cell-to-Cell Contact-Mediated Epstein-Barr Virus TransmissionAsuka Nanbo0Makoto Ohashi1Hironori Yoshiyama2Yusuke Ohba3Department of Cell Physiology, Faculty and Graduate School of Medicine, Hokkaido University, Sapporo, JapanDepartment of Oncology, University of Wisconsin, Madison, WI, United StatesDepartment of Microbiology, Shimane University Faculty of Medicine, Izumo, JapanDepartment of Cell Physiology, Faculty and Graduate School of Medicine, Hokkaido University, Sapporo, JapanInfection of Epstein–Barr virus (EBV), a ubiquitous human gamma herpesvirus, is closely linked to various lymphoid and epithelial malignancies. Previous studies demonstrated that the efficiency of EBV infection in epithelial cells is significantly enhanced by coculturing them with latently infected B cells relative to cell-free infection, suggesting that cell-to-cell contact-mediated viral transmission is the dominant mode of infection by EBV in epithelial cells. However, a detailed mechanism underlying this process has not been fully understood. In the present study, we assessed the role of transforming growth factor β (TGF-β), which is known to induce EBV's lytic cycle by upregulation of EBV's latent-lytic switch BZLF1 gene. We have found that 5 days of cocultivation facilitated cell-to-cell contact-mediated EBV transmission. Replication of EBV was induced in cocultured B cells both with and without a direct cell contact in a time-dependent manner. Treatment of a blocking antibody for TGF-β suppressed both induction of the lytic cycle in cocultured B cells and subsequent viral transmission. Cocultivation with epithelial cells facilitated expression of TGF-β receptors in B cells and increased their susceptibility to TGF-β. Finally, we confirmed the spontaneous secretion of TGF-β from epithelial cells, which was not affected by cell-contact. In contrast, the extracellular microvesicles, exosomes derived from cocultured cells partly contributed to cell-to-cell contact-mediated viral transmission. Taken together, our findings support a role for TGF-β derived from epithelial cells in efficient viral transmission, which fosters induction of the viral lytic cycle in the donor B cells.http://journal.frontiersin.org/article/10.3389/fmicb.2018.00984/fullEpstein-Barr viruscell-to-cell contact-mediated transmissionviral replicationTGF-βexosomes |
collection |
DOAJ |
language |
English |
format |
Article |
sources |
DOAJ |
author |
Asuka Nanbo Makoto Ohashi Hironori Yoshiyama Yusuke Ohba |
spellingShingle |
Asuka Nanbo Makoto Ohashi Hironori Yoshiyama Yusuke Ohba The Role of Transforming Growth Factor β in Cell-to-Cell Contact-Mediated Epstein-Barr Virus Transmission Frontiers in Microbiology Epstein-Barr virus cell-to-cell contact-mediated transmission viral replication TGF-β exosomes |
author_facet |
Asuka Nanbo Makoto Ohashi Hironori Yoshiyama Yusuke Ohba |
author_sort |
Asuka Nanbo |
title |
The Role of Transforming Growth Factor β in Cell-to-Cell Contact-Mediated Epstein-Barr Virus Transmission |
title_short |
The Role of Transforming Growth Factor β in Cell-to-Cell Contact-Mediated Epstein-Barr Virus Transmission |
title_full |
The Role of Transforming Growth Factor β in Cell-to-Cell Contact-Mediated Epstein-Barr Virus Transmission |
title_fullStr |
The Role of Transforming Growth Factor β in Cell-to-Cell Contact-Mediated Epstein-Barr Virus Transmission |
title_full_unstemmed |
The Role of Transforming Growth Factor β in Cell-to-Cell Contact-Mediated Epstein-Barr Virus Transmission |
title_sort |
role of transforming growth factor β in cell-to-cell contact-mediated epstein-barr virus transmission |
publisher |
Frontiers Media S.A. |
series |
Frontiers in Microbiology |
issn |
1664-302X |
publishDate |
2018-05-01 |
description |
Infection of Epstein–Barr virus (EBV), a ubiquitous human gamma herpesvirus, is closely linked to various lymphoid and epithelial malignancies. Previous studies demonstrated that the efficiency of EBV infection in epithelial cells is significantly enhanced by coculturing them with latently infected B cells relative to cell-free infection, suggesting that cell-to-cell contact-mediated viral transmission is the dominant mode of infection by EBV in epithelial cells. However, a detailed mechanism underlying this process has not been fully understood. In the present study, we assessed the role of transforming growth factor β (TGF-β), which is known to induce EBV's lytic cycle by upregulation of EBV's latent-lytic switch BZLF1 gene. We have found that 5 days of cocultivation facilitated cell-to-cell contact-mediated EBV transmission. Replication of EBV was induced in cocultured B cells both with and without a direct cell contact in a time-dependent manner. Treatment of a blocking antibody for TGF-β suppressed both induction of the lytic cycle in cocultured B cells and subsequent viral transmission. Cocultivation with epithelial cells facilitated expression of TGF-β receptors in B cells and increased their susceptibility to TGF-β. Finally, we confirmed the spontaneous secretion of TGF-β from epithelial cells, which was not affected by cell-contact. In contrast, the extracellular microvesicles, exosomes derived from cocultured cells partly contributed to cell-to-cell contact-mediated viral transmission. Taken together, our findings support a role for TGF-β derived from epithelial cells in efficient viral transmission, which fosters induction of the viral lytic cycle in the donor B cells. |
topic |
Epstein-Barr virus cell-to-cell contact-mediated transmission viral replication TGF-β exosomes |
url |
http://journal.frontiersin.org/article/10.3389/fmicb.2018.00984/full |
work_keys_str_mv |
AT asukananbo theroleoftransforminggrowthfactorbincelltocellcontactmediatedepsteinbarrvirustransmission AT makotoohashi theroleoftransforminggrowthfactorbincelltocellcontactmediatedepsteinbarrvirustransmission AT hironoriyoshiyama theroleoftransforminggrowthfactorbincelltocellcontactmediatedepsteinbarrvirustransmission AT yusukeohba theroleoftransforminggrowthfactorbincelltocellcontactmediatedepsteinbarrvirustransmission AT asukananbo roleoftransforminggrowthfactorbincelltocellcontactmediatedepsteinbarrvirustransmission AT makotoohashi roleoftransforminggrowthfactorbincelltocellcontactmediatedepsteinbarrvirustransmission AT hironoriyoshiyama roleoftransforminggrowthfactorbincelltocellcontactmediatedepsteinbarrvirustransmission AT yusukeohba roleoftransforminggrowthfactorbincelltocellcontactmediatedepsteinbarrvirustransmission |
_version_ |
1725855797625225216 |