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However, the mechanisms of neuroinvasion by which the RVF virus (RVFV) reaches the human central nervous system (CNS) remain poorly characterized. In particular, it is not clear how RVFV is able to cross the human blood\u2013brain barrier (hBBB), which is a neurovascular endothelium that protects the brain by regulating brain and blood exchanges. To explore these mechanisms, we used an\n                      <jats:italic>in vitro<\/jats:italic>\n                      hBBB model to mimic\n                      <jats:italic>in vivo<\/jats:italic>\n                      hBBB selectiveness and apicobasal polarity. Our results highlight the ability of RVFV to cross the hBBB by direct infection in a non-structural protein S (NSs)-independent but strain-dependent manner, leading to astrocyte and pericyte infections. Interestingly, RVFV infection did not induce hBBB disruption and was associated with progressive elimination of infected cells with no impairment of the tight junction protein scaffold and barrier function. Our work also shows that NSs, a well described RVFV virulence factor, limited the establishment of the hBBB-induced innate immune response and subsequent lymphocyte recruitment. These results provide\n                      <jats:italic>in vitro<\/jats:italic>\n                      confirmation of the ability of RVFV to reach human CNS by direct infection of the hBBB without altering its barrier function, and provide new directions to explore human RVFV neurovirulence and neuroinvasion mechanisms.\n                    <\/jats:p>\n                    <jats:sec>\n                      <jats:title>IMPORTANCE<\/jats:title>\n                      <jats:p>\n                        The RVF virus (RVFV) is capable of infecting humans and inducing severe and fatal neurological disorders. Neuropathogenesis and human central nervous system (CNS) invasion mechanisms of RVFV are still unknown, with only historical studies of autopsy data from fatal human cases in the 1980s and exploration studies in rodent models. One of the gaps in understanding RVFV human pathogenesis is how RVFV is able to cross the blood\u2013brain barrier (BBB) in order to reach the human CNS. For the first time, we show that RVFV is able to directly infect cells of the human BBB\n                        <jats:italic>in vitro<\/jats:italic>\n                        to release viral particles into the human CNS, a well-characterized neuroinvasion mechanism of pathogens. Furthermore, we demonstrate strain-dependent variability of this neuroinvasion mechanism, identifying possible viral properties that could be explored to prevent neurological disorders during RVFV outbreaks.\n                      <\/jats:p>\n                    <\/jats:sec>\n                  <\/jats:sec>","DOI":"10.1128\/jvi.01267-24","type":"journal-article","created":{"date-parts":[[2024,9,30]],"date-time":"2024-09-30T09:01:51Z","timestamp":1727686911000},"update-policy":"https:\/\/doi.org\/10.1128\/asmj-crossmark-policy-page","source":"Crossref","is-referenced-by-count":14,"title":["Rift Valley fever virus is able to cross the human blood\u2013brain barrier\n                    <i>in vitro<\/i>\n                    by direct infection with no deleterious effects"],"prefix":"10.1128","volume":"98","author":[{"ORCID":"https:\/\/orcid.org\/0000-0003-0414-0572","authenticated-orcid":false,"given":"Jordan","family":"Quellec","sequence":"first","affiliation":[{"name":"ASTRE, CIRAD, INRAE, University of Montpellier, Montpellier, France"},{"name":"PCCEI, University of Montpellier, INSERM, Etablissement Fran\u00e7ais du Sang, Montpellier, France"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Camille","family":"Piro-Megy","sequence":"additional","affiliation":[{"name":"ASTRE, CIRAD, INRAE, University of Montpellier, Montpellier, France"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Marion","family":"Cannac","sequence":"additional","affiliation":[{"name":"IRIM, CNRS UMR9004, University of Montpellier, Montpellier, France"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"S\u00e9bastien","family":"Nisole","sequence":"additional","affiliation":[{"name":"IRIM, CNRS UMR9004, University of Montpellier, Montpellier, France"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Florent H.","family":"Marty","sequence":"additional","affiliation":[{"name":"PCCEI, University of Montpellier, INSERM, Etablissement Fran\u00e7ais du Sang, Montpellier, France"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Fabien","family":"Gosselet","sequence":"additional","affiliation":[{"name":"Blood Brain Barrier Laboratory, Faculty of Science Jean Perrin, Artois University, Lens, France"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Fumitaka","family":"Shimizu","sequence":"additional","affiliation":[{"name":"Department of Neurology and Clinical Neuroscience, Yamaguchi University Graduate School of Medicine, Ube, Japan"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Takashi","family":"Kanda","sequence":"additional","affiliation":[{"name":"Department of Neurology and Clinical Neuroscience, Yamaguchi University Graduate School of Medicine, Ube, Japan"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-0869-1681","authenticated-orcid":true,"given":"Catherine","family":"C\u00eatre-Sossah","sequence":"additional","affiliation":[{"name":"ASTRE, CIRAD, INRAE, University of Montpellier, Montpellier, France"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-4492-2093","authenticated-orcid":true,"given":"Sara","family":"Salinas","sequence":"additional","affiliation":[{"name":"PCCEI, University of Montpellier, INSERM, Etablissement Fran\u00e7ais du Sang, Montpellier, France"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"235","reference":[{"key":"e_1_3_5_2_2","doi-asserted-by":"publisher","DOI":"10.1016\/j.coviro.2017.11.004"},{"key":"e_1_3_5_3_2","doi-asserted-by":"publisher","DOI":"10.1186\/s40249-018-0460-1"},{"key":"e_1_3_5_4_2","doi-asserted-by":"publisher","DOI":"10.1055\/s-0038-1647247"},{"key":"e_1_3_5_5_2","doi-asserted-by":"publisher","DOI":"10.3389\/fneur.2021.634827"},{"key":"e_1_3_5_6_2","doi-asserted-by":"publisher","DOI":"10.1093\/jnen\/nlaa054"},{"key":"e_1_3_5_7_2","doi-asserted-by":"publisher","DOI":"10.1002\/path.1700340418"},{"key":"e_1_3_5_8_2","doi-asserted-by":"publisher","DOI":"10.1099\/jgv.0.001893"},{"key":"e_1_3_5_9_2","doi-asserted-by":"publisher","DOI":"10.1007\/s00705-019-04253-6"},{"key":"e_1_3_5_10_2","doi-asserted-by":"publisher","DOI":"10.1099\/jgv.0.001296"},{"key":"e_1_3_5_11_2","doi-asserted-by":"publisher","DOI":"10.1016\/j.antiviral.2018.05.009"},{"key":"e_1_3_5_12_2","doi-asserted-by":"publisher","DOI":"10.3390\/pathogens10060708"},{"key":"e_1_3_5_13_2","doi-asserted-by":"publisher","DOI":"10.1016\/j.scitotenv.2024.170302"},{"key":"e_1_3_5_14_2","doi-asserted-by":"publisher","DOI":"10.2478\/jvetres-2021-0009"},{"key":"e_1_3_5_15_2","doi-asserted-by":"publisher","DOI":"10.1093\/jme\/tjad113"},{"key":"e_1_3_5_16_2","doi-asserted-by":"publisher","DOI":"10.1073\/pnas.2004468117"},{"key":"e_1_3_5_17_2","first-page":"803","article-title":"Rift Valley fever in humans in South Africa","volume":"58","author":"McIntosh BM","year":"1980","unstructured":"McIntosh BM, Russell D, dos Santos I, Gear JH. 1980. 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