Cargando…
Age influences susceptibility of brain capillary endothelial cells to La Crosse virus infection and cell death
BACKGROUND: A key factor in the development of viral encephalitis is a virus crossing the blood-brain barrier (BBB). We have previously shown that age-related susceptibility of mice to the La Crosse virus (LACV), the leading cause of pediatric arbovirus encephalitis in the USA, was associated with t...
Autores principales: | , , , , , |
---|---|
Formato: | Online Artículo Texto |
Lenguaje: | English |
Publicado: |
BioMed Central
2021
|
Materias: | |
Acceso en línea: | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC8173794/ https://www.ncbi.nlm.nih.gov/pubmed/34082753 http://dx.doi.org/10.1186/s12974-021-02173-4 |
_version_ | 1783702779249819648 |
---|---|
author | Basu, Rahul Nair, Vinod Winkler, Clayton W. Woods, Tyson A. Fraser, Iain D. C. Peterson, Karin E. |
author_facet | Basu, Rahul Nair, Vinod Winkler, Clayton W. Woods, Tyson A. Fraser, Iain D. C. Peterson, Karin E. |
author_sort | Basu, Rahul |
collection | PubMed |
description | BACKGROUND: A key factor in the development of viral encephalitis is a virus crossing the blood-brain barrier (BBB). We have previously shown that age-related susceptibility of mice to the La Crosse virus (LACV), the leading cause of pediatric arbovirus encephalitis in the USA, was associated with the ability of the virus to cross the BBB. LACV infection in weanling mice (aged around 3 weeks) results in vascular leakage in the olfactory bulb/tract (OB/OT) region of the brain, which is not observed in adult mice aged > 6–8 weeks. Thus, we studied age-specific differences in the response of brain capillary endothelial cells (BCECs) to LACV infection. METHODS: To examine mechanisms of LACV-induced BBB breakdown and infection of the CNS, we analyzed BCECs directly isolated from weanling and adult mice as well as established a model where these cells were infected in vitro and cultured for a short period to determine susceptibility to virus infection and cell death. Additionally, we utilized correlative light electron microscopy (CLEM) to examine whether changes in cell morphology and function were also observed in BCECs in vivo. RESULTS: BCECs from weanling, but not adult mice, had detectable infection after several days in culture when taken ex vivo from infected mice suggesting that these cells could be infected in vitro. Further analysis of BCECs from uninfected mice, infected in vitro, showed that weanling BCECs were more susceptible to virus infection than adult BCECs, with higher levels of infected cells, released virus as well as cytopathic effects (CPE) and cell death. Although direct LACV infection is not detected in the weanling BCECs, CLEM analysis of brain tissue from weanling mice indicated that LACV infection induced significant cerebrovascular damage which allowed virus-sized particles to enter the brain parenchyma. CONCLUSIONS: These findings indicate that BCECs isolated from adult and weanling mice have differential viral load, infectivity, and susceptibility to LACV. These age-related differences in susceptibility may strongly influence LACV-induced BBB leakage and neurovascular damage allowing virus invasion of the CNS and the development of neurological disease. SUPPLEMENTARY INFORMATION: The online version contains supplementary material available at 10.1186/s12974-021-02173-4. |
format | Online Article Text |
id | pubmed-8173794 |
institution | National Center for Biotechnology Information |
language | English |
publishDate | 2021 |
publisher | BioMed Central |
record_format | MEDLINE/PubMed |
spelling | pubmed-81737942021-06-03 Age influences susceptibility of brain capillary endothelial cells to La Crosse virus infection and cell death Basu, Rahul Nair, Vinod Winkler, Clayton W. Woods, Tyson A. Fraser, Iain D. C. Peterson, Karin E. J Neuroinflammation Research BACKGROUND: A key factor in the development of viral encephalitis is a virus crossing the blood-brain barrier (BBB). We have previously shown that age-related susceptibility of mice to the La Crosse virus (LACV), the leading cause of pediatric arbovirus encephalitis in the USA, was associated with the ability of the virus to cross the BBB. LACV infection in weanling mice (aged around 3 weeks) results in vascular leakage in the olfactory bulb/tract (OB/OT) region of the brain, which is not observed in adult mice aged > 6–8 weeks. Thus, we studied age-specific differences in the response of brain capillary endothelial cells (BCECs) to LACV infection. METHODS: To examine mechanisms of LACV-induced BBB breakdown and infection of the CNS, we analyzed BCECs directly isolated from weanling and adult mice as well as established a model where these cells were infected in vitro and cultured for a short period to determine susceptibility to virus infection and cell death. Additionally, we utilized correlative light electron microscopy (CLEM) to examine whether changes in cell morphology and function were also observed in BCECs in vivo. RESULTS: BCECs from weanling, but not adult mice, had detectable infection after several days in culture when taken ex vivo from infected mice suggesting that these cells could be infected in vitro. Further analysis of BCECs from uninfected mice, infected in vitro, showed that weanling BCECs were more susceptible to virus infection than adult BCECs, with higher levels of infected cells, released virus as well as cytopathic effects (CPE) and cell death. Although direct LACV infection is not detected in the weanling BCECs, CLEM analysis of brain tissue from weanling mice indicated that LACV infection induced significant cerebrovascular damage which allowed virus-sized particles to enter the brain parenchyma. CONCLUSIONS: These findings indicate that BCECs isolated from adult and weanling mice have differential viral load, infectivity, and susceptibility to LACV. These age-related differences in susceptibility may strongly influence LACV-induced BBB leakage and neurovascular damage allowing virus invasion of the CNS and the development of neurological disease. SUPPLEMENTARY INFORMATION: The online version contains supplementary material available at 10.1186/s12974-021-02173-4. BioMed Central 2021-06-03 /pmc/articles/PMC8173794/ /pubmed/34082753 http://dx.doi.org/10.1186/s12974-021-02173-4 Text en © The Author(s) 2021 https://creativecommons.org/licenses/by/4.0/Open AccessThis article is licensed under a Creative Commons Attribution 4.0 International License, which permits use, sharing, adaptation, distribution and reproduction in any medium or format, as long as you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons licence, and indicate if changes were made. The images or other third party material in this article are included in the article's Creative Commons licence, unless indicated otherwise in a credit line to the material. If material is not included in the article's Creative Commons licence and your intended use is not permitted by statutory regulation or exceeds the permitted use, you will need to obtain permission directly from the copyright holder. To view a copy of this licence, visit http://creativecommons.org/licenses/by/4.0/ (https://creativecommons.org/licenses/by/4.0/) . The Creative Commons Public Domain Dedication waiver (http://creativecommons.org/publicdomain/zero/1.0/ (https://creativecommons.org/publicdomain/zero/1.0/) ) applies to the data made available in this article, unless otherwise stated in a credit line to the data. |
spellingShingle | Research Basu, Rahul Nair, Vinod Winkler, Clayton W. Woods, Tyson A. Fraser, Iain D. C. Peterson, Karin E. Age influences susceptibility of brain capillary endothelial cells to La Crosse virus infection and cell death |
title | Age influences susceptibility of brain capillary endothelial cells to La Crosse virus infection and cell death |
title_full | Age influences susceptibility of brain capillary endothelial cells to La Crosse virus infection and cell death |
title_fullStr | Age influences susceptibility of brain capillary endothelial cells to La Crosse virus infection and cell death |
title_full_unstemmed | Age influences susceptibility of brain capillary endothelial cells to La Crosse virus infection and cell death |
title_short | Age influences susceptibility of brain capillary endothelial cells to La Crosse virus infection and cell death |
title_sort | age influences susceptibility of brain capillary endothelial cells to la crosse virus infection and cell death |
topic | Research |
url | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC8173794/ https://www.ncbi.nlm.nih.gov/pubmed/34082753 http://dx.doi.org/10.1186/s12974-021-02173-4 |
work_keys_str_mv | AT basurahul ageinfluencessusceptibilityofbraincapillaryendothelialcellstolacrossevirusinfectionandcelldeath AT nairvinod ageinfluencessusceptibilityofbraincapillaryendothelialcellstolacrossevirusinfectionandcelldeath AT winklerclaytonw ageinfluencessusceptibilityofbraincapillaryendothelialcellstolacrossevirusinfectionandcelldeath AT woodstysona ageinfluencessusceptibilityofbraincapillaryendothelialcellstolacrossevirusinfectionandcelldeath AT fraseriaindc ageinfluencessusceptibilityofbraincapillaryendothelialcellstolacrossevirusinfectionandcelldeath AT petersonkarine ageinfluencessusceptibilityofbraincapillaryendothelialcellstolacrossevirusinfectionandcelldeath |