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Coxsackievirus B3 infects and disrupts human induced-pluripotent stem cell derived brain-like endothelial cells
Coxsackievirus B3 (CVB3) is a significant human pathogen that is commonly found worldwide. CVB3 among other enteroviruses, are the leading causes of aseptic meningo-encephalitis which can be fatal especially in young children. How the virus gains access to the brain is poorly-understood, and the hos...
Autores principales: | , , , , , , |
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Formato: | Online Artículo Texto |
Lenguaje: | English |
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Frontiers Media S.A.
2023
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Acceso en línea: | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC10149843/ https://www.ncbi.nlm.nih.gov/pubmed/37139492 http://dx.doi.org/10.3389/fcimb.2023.1171275 |
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author | Mamana, Julia Humber, Gabrielle M. Espinal, Eric R. Seo, Soojung Vollmuth, Nadine Sin, Jon Kim, Brandon J. |
author_facet | Mamana, Julia Humber, Gabrielle M. Espinal, Eric R. Seo, Soojung Vollmuth, Nadine Sin, Jon Kim, Brandon J. |
author_sort | Mamana, Julia |
collection | PubMed |
description | Coxsackievirus B3 (CVB3) is a significant human pathogen that is commonly found worldwide. CVB3 among other enteroviruses, are the leading causes of aseptic meningo-encephalitis which can be fatal especially in young children. How the virus gains access to the brain is poorly-understood, and the host-virus interactions that occur at the blood-brain barrier (BBB) is even less-characterized. The BBB is a highly specialized biological barrier consisting primarily of brain endothelial cells which possess unique barrier properties and facilitate the passage of nutrients into the brain while restricting access to toxins and pathogens including viruses. To determine the effects of CVB3 infection on the BBB, we utilized a model of human induced-pluripotent stem cell-derived brain-like endothelial cells (iBECs) to ascertain if CVB3 infection may alter barrier cell function and overall survival. In this study, we determined that these iBECs indeed are susceptible to CVB3 infection and release high titers of extracellular virus. We also determined that infected iBECs maintain high transendothelial electrical resistance (TEER) during early infection despite possessing high viral load. TEER progressively declines at later stages of infection. Interestingly, despite the high viral burden and TEER disruptions at later timepoints, infected iBEC monolayers remain intact, indicating a low degree of late-stage virally-mediated cell death, which may contribute to prolonged viral shedding. We had previously reported that CVB3 infections rely on the activation of transient receptor vanilloid potential 1 (TRPV1) and found that inhibiting TRPV1 activity with SB-366791 significantly limited CVB3 infection of HeLa cervical cancer cells. Similarly in this study, we observed that treating iBECs with SB-366791 significantly reduced CVB3 infection, which suggests that not only can this drug potentially limit viral entry into the brain, but also demonstrates that this infection model could be a valuable platform for testing antiviral treatments of neurotropic viruses. In all, our findings elucidate the unique effects of CVB3 infection on the BBB and shed light on potential mechanisms by which the virus can initiate infections in the brain. |
format | Online Article Text |
id | pubmed-10149843 |
institution | National Center for Biotechnology Information |
language | English |
publishDate | 2023 |
publisher | Frontiers Media S.A. |
record_format | MEDLINE/PubMed |
spelling | pubmed-101498432023-05-02 Coxsackievirus B3 infects and disrupts human induced-pluripotent stem cell derived brain-like endothelial cells Mamana, Julia Humber, Gabrielle M. Espinal, Eric R. Seo, Soojung Vollmuth, Nadine Sin, Jon Kim, Brandon J. Front Cell Infect Microbiol Cellular and Infection Microbiology Coxsackievirus B3 (CVB3) is a significant human pathogen that is commonly found worldwide. CVB3 among other enteroviruses, are the leading causes of aseptic meningo-encephalitis which can be fatal especially in young children. How the virus gains access to the brain is poorly-understood, and the host-virus interactions that occur at the blood-brain barrier (BBB) is even less-characterized. The BBB is a highly specialized biological barrier consisting primarily of brain endothelial cells which possess unique barrier properties and facilitate the passage of nutrients into the brain while restricting access to toxins and pathogens including viruses. To determine the effects of CVB3 infection on the BBB, we utilized a model of human induced-pluripotent stem cell-derived brain-like endothelial cells (iBECs) to ascertain if CVB3 infection may alter barrier cell function and overall survival. In this study, we determined that these iBECs indeed are susceptible to CVB3 infection and release high titers of extracellular virus. We also determined that infected iBECs maintain high transendothelial electrical resistance (TEER) during early infection despite possessing high viral load. TEER progressively declines at later stages of infection. Interestingly, despite the high viral burden and TEER disruptions at later timepoints, infected iBEC monolayers remain intact, indicating a low degree of late-stage virally-mediated cell death, which may contribute to prolonged viral shedding. We had previously reported that CVB3 infections rely on the activation of transient receptor vanilloid potential 1 (TRPV1) and found that inhibiting TRPV1 activity with SB-366791 significantly limited CVB3 infection of HeLa cervical cancer cells. Similarly in this study, we observed that treating iBECs with SB-366791 significantly reduced CVB3 infection, which suggests that not only can this drug potentially limit viral entry into the brain, but also demonstrates that this infection model could be a valuable platform for testing antiviral treatments of neurotropic viruses. In all, our findings elucidate the unique effects of CVB3 infection on the BBB and shed light on potential mechanisms by which the virus can initiate infections in the brain. Frontiers Media S.A. 2023-04-17 /pmc/articles/PMC10149843/ /pubmed/37139492 http://dx.doi.org/10.3389/fcimb.2023.1171275 Text en Copyright © 2023 Mamana, Humber, Espinal, Seo, Vollmuth, Sin and Kim https://creativecommons.org/licenses/by/4.0/This is an open-access article distributed under the terms of the Creative Commons Attribution License (CC BY). The use, distribution or reproduction in other forums is permitted, provided the original author(s) and the copyright owner(s) are credited and that the original publication in this journal is cited, in accordance with accepted academic practice. No use, distribution or reproduction is permitted which does not comply with these terms. |
spellingShingle | Cellular and Infection Microbiology Mamana, Julia Humber, Gabrielle M. Espinal, Eric R. Seo, Soojung Vollmuth, Nadine Sin, Jon Kim, Brandon J. Coxsackievirus B3 infects and disrupts human induced-pluripotent stem cell derived brain-like endothelial cells |
title | Coxsackievirus B3 infects and disrupts human induced-pluripotent stem cell derived brain-like endothelial cells |
title_full | Coxsackievirus B3 infects and disrupts human induced-pluripotent stem cell derived brain-like endothelial cells |
title_fullStr | Coxsackievirus B3 infects and disrupts human induced-pluripotent stem cell derived brain-like endothelial cells |
title_full_unstemmed | Coxsackievirus B3 infects and disrupts human induced-pluripotent stem cell derived brain-like endothelial cells |
title_short | Coxsackievirus B3 infects and disrupts human induced-pluripotent stem cell derived brain-like endothelial cells |
title_sort | coxsackievirus b3 infects and disrupts human induced-pluripotent stem cell derived brain-like endothelial cells |
topic | Cellular and Infection Microbiology |
url | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC10149843/ https://www.ncbi.nlm.nih.gov/pubmed/37139492 http://dx.doi.org/10.3389/fcimb.2023.1171275 |
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