Hepatitis E virus infects brain microvascular endothelial cells, crosses the blood–brain barrier, and invades the central nervous system

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dc.contributor.authorTian, Debinen
dc.contributor.authorLi, Wenen
dc.contributor.authorHeffron, C. Lynnen
dc.contributor.authorWang, Boen
dc.contributor.authorMahsoub, Hassan M.en
dc.contributor.authorSooryanarain, Harinien
dc.contributor.authorHassebroek, Anna M.en
dc.contributor.authorClark-Deener, Sherrieen
dc.contributor.authorLeRoith, Tanyaen
dc.contributor.authorMeng, Xiang-Jinen
dc.date.accessioned2023-01-04T18:22:10Zen
dc.date.available2023-01-04T18:22:10Zen
dc.date.issued2022-06-14en
dc.date.updated2023-01-03T14:44:31Zen
dc.description.abstractHepatitis E virus (HEV) is an important but understudied zoonotic virus causing both acute and chronic viral hepatitis. A proportion of HEV-infected individuals also developed neurological diseases such as Guillain–Barre syndrome, neuralgic amyotrophy, encephalitis, and myelitis, although the mechanism remains unknown. In this study, by using an in vitro blood–brain barrier (BBB) model, we first investigated whether HEV can cross the BBB and whether the quasi-enveloped HEV virions are more permissible to the BBB than the nonenveloped virions. We found that both quasi-enveloped and nonenveloped HEVs can similarly cross the BBB and that addition of proinflammatory cytokine tumor necrosis factor alpha (TNF-α) has no significant effect on the ability of HEV to cross the BBB in vitro. To explore the possible mechanism of HEV entry across the BBB, we tested the susceptibility of human brain microvascular endothelial cells lining the BBB to HEV infection and showed that brain microvascular endothelial cells support productive HEV infection. To further confirm the in vitro observation, we conducted an experimental HEV infection study in pigs and showed that both quasi-enveloped and nonenveloped HEVs invade the central nervous system (CNS) in pigs, as HEV RNA was detected in the brain and spinal cord of infected pigs. The HEV-infected pigs with detectable viral RNA in CNS tissues had histological lesions in brain and spinal cord and significantly higher levels of proinflammatory cytokines TNF-α and interleukin 18 than the HEV-infected pigs without detectable viral RNA in CNS tissues. The findings suggest a potential mechanism of HEV-associated neuroinvasion.en
dc.description.versionPublished versionen
dc.format.mimetypeapplication/pdfen
dc.identifier.doihttps://doi.org/10.1073/pnas.2201862119en
dc.identifier.eissn1091-6490en
dc.identifier.issn0027-8424en
dc.identifier.issue24en
dc.identifier.orcidLeRoith, Tanya [0000-0002-1196-6949]en
dc.identifier.orcidLi, Wen [0000-0002-5543-4899]en
dc.identifier.orcidMeng, Xiang-Jin [0000-0002-2739-1334]en
dc.identifier.orcidClark-Deener, Sherrie [0000-0001-9206-6434] [0000-0002-6620-0625]en
dc.identifier.pmid35671427en
dc.identifier.urihttp://hdl.handle.net/10919/113028en
dc.identifier.volume119en
dc.language.isoenen
dc.publisherProceedings of the National Academy of Sciencesen
dc.relation.urihttps://www.ncbi.nlm.nih.gov/pubmed/35671427en
dc.rightsCreative Commons Attribution-NonCommercial-NoDerivatives 4.0 Internationalen
dc.rights.urihttp://creativecommons.org/licenses/by-nc-nd/4.0/en
dc.subjectblood–brain barrier (BBB)en
dc.subjectbrain microvascular endothelial cellsen
dc.subjectcentral nervous system (CNS)en
dc.subjecthepatitis E virus (HEV)en
dc.subjectneurological disorderen
dc.subjectNeurodegenerativeen
dc.subjectLiver Diseaseen
dc.subjectNeurosciencesen
dc.subjectHepatitisen
dc.subjectInfectious Diseasesen
dc.subjectDigestive Diseasesen
dc.subjectBrain Disordersen
dc.subjectEmerging Infectious Diseasesen
dc.subject2.1 Biological and endogenous factorsen
dc.subject2 Aetiologyen
dc.subjectInfectionen
dc.subjectNeurologicalen
dc.subject.meshBlood-Brain Barrieren
dc.subject.meshCentral Nervous Systemen
dc.subject.meshEndothelial Cellsen
dc.subject.meshAnimalsen
dc.subject.meshSwineen
dc.subject.meshHumansen
dc.subject.meshHepatitis E virusen
dc.subject.meshHepatitis Een
dc.subject.meshTumor Necrosis Factor-alphaen
dc.subject.meshRNA, Viralen
dc.titleHepatitis E virus infects brain microvascular endothelial cells, crosses the blood–brain barrier, and invades the central nervous systemen
dc.title.serialProceedings of the National Academy of Sciences of the United States of Americaen
dc.typeArticle - Refereeden
dc.type.dcmitypeTexten
dc.type.otherJournal Articleen
pubs.organisational-group/Virginia Techen
pubs.organisational-group/Virginia Tech/Veterinary Medicineen
pubs.organisational-group/Virginia Tech/Veterinary Medicine/Biomedical Sciences and Pathobiologyen
pubs.organisational-group/Virginia Tech/Veterinary Medicine/Large Animal Clinical Sciencesen
pubs.organisational-group/Virginia Tech/University Distinguished Professorsen
pubs.organisational-group/Virginia Tech/Faculty of Health Sciencesen
pubs.organisational-group/Virginia Tech/All T&R Facultyen
pubs.organisational-group/Virginia Tech/Veterinary Medicine/CVM T&R Facultyen
pubs.organisational-group/Virginia Tech/VT Carilion School of Medicineen
pubs.organisational-group/Virginia Tech/VT Carilion School of Medicine/Internal Medicineen
pubs.organisational-group/Virginia Tech/VT Carilion School of Medicine/Internal Medicine/Internal Med-Subgroupen

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