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Responsible for the current coronavirus disease (COVID-19) pandemic, SARS-CoV-2 may access and affect the central nervous system (CNS) by several pathways such as axonal retrograde transport or through interaction with the blood-brain barrier (BBB) or blood-cerebrospinal fluid (CSF) barrier. Here, we explored the molecular and cellular effects of direct SARS-CoV-2 infection of human BBB cells. We observed low replication of SARS-CoV-2 that was accompanied by very moderate inflammatory response. Using a human <jats:italic>in vitro<\/jats:italic> BBB model, we also described low replication levels without strong inflammatory response or modulation of endothelium integrity. Finally, using serum samples from COVID-19 patients, we highlighted strong concentrations of pro-inflammatory factors that did not perturb BBB integrity after short term exposure. Altogether, our results show that the main mechanism of brain access following SARS-CoV-2 infection does not seem to be directed by brain infection through endothelial cells.<\/jats:p>","DOI":"10.3389\/fimmu.2021.697329","type":"journal-article","created":{"date-parts":[[2021,7,27]],"date-time":"2021-07-27T08:51:07Z","timestamp":1627375867000},"update-policy":"https:\/\/doi.org\/10.3389\/crossmark-policy","source":"Crossref","is-referenced-by-count":38,"title":["SARS-CoV-2 Poorly Replicates in Cells of the Human Blood-Brain Barrier Without Associated Deleterious Effects"],"prefix":"10.3389","volume":"12","author":[{"given":"Orianne","family":"Constant","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jonathan","family":"Barthelemy","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Karine","family":"Bollor\u00e9","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Edouard","family":"Tuaillon","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Fabien","family":"Gosselet","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Christine","family":"Chable-Bessia","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Peggy","family":"Merida","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Delphine","family":"Muriaux","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Philippe","family":"Van de Perre","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Sara","family":"Salinas","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yannick","family":"Simonin","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1965","published-online":{"date-parts":[[2021,7,27]]},"reference":[{"key":"B1","doi-asserted-by":"publisher","DOI":"10.1038\/s41586-020-2008-3","article-title":"A New Coronavirus Associated With Human Respiratory Disease in China","volume":"579","author":"Wu","year":"2020","journal-title":"Nature"},{"key":"B2","doi-asserted-by":"publisher","DOI":"10.1016\/S0140-6736(20)30251-8","article-title":"Genomic Characterisation and Epidemiology of 2019 Novel Coronavirus: Implications for Virus Origins and Receptor Binding","volume":"395","author":"Lu","year":"2020","journal-title":"Lancet"},{"key":"B3","doi-asserted-by":"publisher","DOI":"10.1038\/nature02145","article-title":"Angiotensin-Converting Enzyme 2 Is a Functional Receptor for the SARS Coronavirus","volume":"426","author":"Li","year":"2003","journal-title":"Nature"},{"key":"B4","doi-asserted-by":"publisher","first-page":"497","DOI":"10.1016\/S0140-6736(20)30183-5","article-title":"Clinical Features of Patients Infected With 2019 Novel Coronavirus in Wuhan, China","volume":"395","author":"Huang","year":"2020","journal-title":"Lancet"},{"key":"B5","doi-asserted-by":"publisher","DOI":"10.1177\/1073858420941476","article-title":"COVID-19, Mast Cells, Cytokine Storm, Psychological Stress, and Neuroinflammation","volume":"26","author":"Kempuraj","year":"2020","journal-title":"Neuroscientist"},{"key":"B6","doi-asserted-by":"publisher","DOI":"10.1172\/JCI137244","article-title":"Clinical and Immunological Features of Severe and Moderate Coronavirus Disease 2019","volume":"130","author":"Chen","year":"2020","journal-title":"J\u00a0Clin Invest"},{"key":"B7","doi-asserted-by":"publisher","first-page":"1","DOI":"10.1111\/ene.14277","article-title":"Does SARS-Cov-2 Invade the Brain? 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