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Natl. Acad. Sci. U.S.A."],"published-print":{"date-parts":[[2022,6,14]]},"abstract":"<jats:p>Hepatitis 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\u2013Barr\u00e9 syndrome, neuralgic amyotrophy, encephalitis, and myelitis, although the mechanism remains unknown. In this study, by using an in\u00a0vitro blood\u2013brain 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-\u03b1) has no significant effect on the ability of HEV to cross the BBB in\u00a0vitro. 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\u00a0vitro 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-\u03b1 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.<\/jats:p>","DOI":"10.1073\/pnas.2201862119","type":"journal-article","created":{"date-parts":[[2022,6,7]],"date-time":"2022-06-07T16:28:44Z","timestamp":1654619324000},"update-policy":"https:\/\/doi.org\/10.1073\/pnas.cm10313","source":"Crossref","is-referenced-by-count":51,"title":["Hepatitis E virus infects brain microvascular endothelial cells, crosses the blood\u2013brain barrier, and invades the central nervous system"],"prefix":"10.1073","volume":"119","author":[{"ORCID":"https:\/\/orcid.org\/0000-0002-5897-5519","authenticated-orcid":false,"given":"Debin","family":"Tian","sequence":"first","affiliation":[{"name":"Department of Biomedical Sciences and Pathobiology, Virginia\u2013Maryland College of Veterinary Medicine, Virginia Polytechnic Institute and State University, Blacksburg, VA 24061"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Wen","family":"Li","sequence":"additional","affiliation":[{"name":"Department of Biomedical Sciences and Pathobiology, Virginia\u2013Maryland College of Veterinary Medicine, Virginia Polytechnic Institute and State University, Blacksburg, VA 24061"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"C. 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