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Human Gut-On-A-Chip Supports Polarized Infection of Coxsackie B1 Virus In Vitro

Analysis of enterovirus infection is difficult in animals because they express different virus receptors than humans, and static cell culture systems do not reproduce the physical complexity of the human intestinal epithelium. Here, using coxsackievirus B1 (CVB1) as a prototype enterovirus strain, w...

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Autores principales: Villenave, Remi, Wales, Samantha Q., Hamkins-Indik, Tiama, Papafragkou, Efstathia, Weaver, James C., Ferrante, Thomas C., Bahinski, Anthony, Elkins, Christopher A., Kulka, Michael, Ingber, Donald E.
Formato: Online Artículo Texto
Lenguaje:English
Publicado: Public Library of Science 2017
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5287454/
https://www.ncbi.nlm.nih.gov/pubmed/28146569
http://dx.doi.org/10.1371/journal.pone.0169412
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author Villenave, Remi
Wales, Samantha Q.
Hamkins-Indik, Tiama
Papafragkou, Efstathia
Weaver, James C.
Ferrante, Thomas C.
Bahinski, Anthony
Elkins, Christopher A.
Kulka, Michael
Ingber, Donald E.
author_facet Villenave, Remi
Wales, Samantha Q.
Hamkins-Indik, Tiama
Papafragkou, Efstathia
Weaver, James C.
Ferrante, Thomas C.
Bahinski, Anthony
Elkins, Christopher A.
Kulka, Michael
Ingber, Donald E.
author_sort Villenave, Remi
collection PubMed
description Analysis of enterovirus infection is difficult in animals because they express different virus receptors than humans, and static cell culture systems do not reproduce the physical complexity of the human intestinal epithelium. Here, using coxsackievirus B1 (CVB1) as a prototype enterovirus strain, we demonstrate that human enterovirus infection, replication and infectious virus production can be analyzed in vitro in a human Gut-on-a-Chip microfluidic device that supports culture of highly differentiated human villus intestinal epithelium under conditions of fluid flow and peristalsis-like motions. When CVB1 was introduced into the epithelium-lined intestinal lumen of the device, virions entered the epithelium, replicated inside the cells producing detectable cytopathic effects (CPEs), and both infectious virions and inflammatory cytokines were released in a polarized manner from the cell apex, as they could be detected in the effluent from the epithelial microchannel. When the virus was introduced via a basal route of infection (by inoculating virus into fluid flowing through a parallel lower ‘vascular’ channel separated from the epithelial channel by a porous membrane), significantly lower viral titers, decreased CPEs, and delayed caspase-3 activation were observed; however, cytokines continued to be secreted apically. The presence of continuous fluid flow through the epithelial lumen also resulted in production of a gradient of CPEs consistent with the flow direction. Thus, the human Gut-on-a-Chip may provide a suitable in vitro model for enteric virus infection and for investigating mechanisms of enterovirus pathogenesis.
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spelling pubmed-52874542017-02-17 Human Gut-On-A-Chip Supports Polarized Infection of Coxsackie B1 Virus In Vitro Villenave, Remi Wales, Samantha Q. Hamkins-Indik, Tiama Papafragkou, Efstathia Weaver, James C. Ferrante, Thomas C. Bahinski, Anthony Elkins, Christopher A. Kulka, Michael Ingber, Donald E. PLoS One Research Article Analysis of enterovirus infection is difficult in animals because they express different virus receptors than humans, and static cell culture systems do not reproduce the physical complexity of the human intestinal epithelium. Here, using coxsackievirus B1 (CVB1) as a prototype enterovirus strain, we demonstrate that human enterovirus infection, replication and infectious virus production can be analyzed in vitro in a human Gut-on-a-Chip microfluidic device that supports culture of highly differentiated human villus intestinal epithelium under conditions of fluid flow and peristalsis-like motions. When CVB1 was introduced into the epithelium-lined intestinal lumen of the device, virions entered the epithelium, replicated inside the cells producing detectable cytopathic effects (CPEs), and both infectious virions and inflammatory cytokines were released in a polarized manner from the cell apex, as they could be detected in the effluent from the epithelial microchannel. When the virus was introduced via a basal route of infection (by inoculating virus into fluid flowing through a parallel lower ‘vascular’ channel separated from the epithelial channel by a porous membrane), significantly lower viral titers, decreased CPEs, and delayed caspase-3 activation were observed; however, cytokines continued to be secreted apically. The presence of continuous fluid flow through the epithelial lumen also resulted in production of a gradient of CPEs consistent with the flow direction. Thus, the human Gut-on-a-Chip may provide a suitable in vitro model for enteric virus infection and for investigating mechanisms of enterovirus pathogenesis. Public Library of Science 2017-02-01 /pmc/articles/PMC5287454/ /pubmed/28146569 http://dx.doi.org/10.1371/journal.pone.0169412 Text en https://creativecommons.org/publicdomain/zero/1.0/ This is an open access article, free of all copyright, and may be freely reproduced, distributed, transmitted, modified, built upon, or otherwise used by anyone for any lawful purpose. The work is made available under the Creative Commons CC0 (https://creativecommons.org/publicdomain/zero/1.0/) public domain dedication.
spellingShingle Research Article
Villenave, Remi
Wales, Samantha Q.
Hamkins-Indik, Tiama
Papafragkou, Efstathia
Weaver, James C.
Ferrante, Thomas C.
Bahinski, Anthony
Elkins, Christopher A.
Kulka, Michael
Ingber, Donald E.
Human Gut-On-A-Chip Supports Polarized Infection of Coxsackie B1 Virus In Vitro
title Human Gut-On-A-Chip Supports Polarized Infection of Coxsackie B1 Virus In Vitro
title_full Human Gut-On-A-Chip Supports Polarized Infection of Coxsackie B1 Virus In Vitro
title_fullStr Human Gut-On-A-Chip Supports Polarized Infection of Coxsackie B1 Virus In Vitro
title_full_unstemmed Human Gut-On-A-Chip Supports Polarized Infection of Coxsackie B1 Virus In Vitro
title_short Human Gut-On-A-Chip Supports Polarized Infection of Coxsackie B1 Virus In Vitro
title_sort human gut-on-a-chip supports polarized infection of coxsackie b1 virus in vitro
topic Research Article
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5287454/
https://www.ncbi.nlm.nih.gov/pubmed/28146569
http://dx.doi.org/10.1371/journal.pone.0169412
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