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Meningitis is initiated by the transfer of <jats:italic>S. pneumoniae<\/jats:italic> from blood to the brain across the blood\u2013cerebrospinal fluid barrier or the blood\u2013brain barrier (BBB). The underlying mechanisms are still poorly understood. Current treatment strategies include adjuvant dexamethasone for inflammation and cerebral edema, followed by antibiotics. The success of dexamethasone is however inconclusive, necessitating new therapies for controlling edema, the primary reason for neurological complications. Since we have previously shown a general activation of hypoxia inducible factor (HIF-1\u03b1) in bacterial infections, we hypothesized that HIF-1\u03b1, via induction of vascular endothelial growth factor (VEGF) is involved in transmigration of pathogens across the BBB. In human, murine meningitis brain samples, HIF-1\u03b1 activation was observed by immunohistochemistry. <jats:italic>S. pneumoniae<\/jats:italic> infection in brain endothelial cells (EC) resulted in in vitro upregulation of HIF-1\u03b1\/VEGF (Western blotting\/qRT-PCR) associated with increased paracellular permeability (fluorometry, impedance measurements). This was supported by bacterial localization at cell\u2013cell junctions in vitro and in vivo in brain ECs from mouse and humans (confocal, super-resolution, electron microscopy, live-cell imaging). Hematogenously infected mice showed increased permeability, <jats:italic>S. pneumoniae<\/jats:italic> deposition in the brain, along with upregulation of genes in the HIF-1\u03b1\/VEGF pathway (RNA sequencing of brain microvessels). Inhibition of HIF-1\u03b1 with echinomycin, <jats:italic>si<\/jats:italic>RNA in bEnd5 cells or using primary brain ECs from HIF-1\u03b1 knock-out mice revealed reduced endothelial permeability and transmigration of <jats:italic>S. pneumoniae<\/jats:italic>. Therapeutic rescue using the HIF-1\u03b1 inhibitor echinomycin resulted in increased survival and improvement of BBB function in <jats:italic>S. pneumoniae<\/jats:italic>-infected mice. We thus demonstrate paracellular migration of bacteria across BBB and a critical role for HIF-1\u03b1\/VEGF therein and hence propose targeting this pathway to prevent BBB dysfunction and ensuing brain damage in infections.<\/jats:p>","DOI":"10.1007\/s00401-020-02174-2","type":"journal-article","created":{"date-parts":[[2020,6,11]],"date-time":"2020-06-11T07:02:23Z","timestamp":1591858943000},"page":"183-208","update-policy":"https:\/\/doi.org\/10.1007\/springer_crossmark_policy","source":"Crossref","is-referenced-by-count":45,"title":["HIF-1\u03b1 is involved in blood\u2013brain barrier dysfunction and paracellular migration of bacteria in pneumococcal meningitis"],"prefix":"10.1007","volume":"140","author":[{"given":"Gayatri","family":"Devraj","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Sylvaine","family":"Gu\u00e9rit","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jana","family":"Seele","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Daniel","family":"Spitzer","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jadranka","family":"Macas","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Maryam I.","family":"Khel","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Roxana","family":"Heidemann","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Anne K.","family":"Braczynski","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Wibke","family":"Ballhorn","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Stefan","family":"G\u00fcnther","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Omolara O.","family":"Ogunshola","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Michel","family":"Mittelbronn","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Uwe","family":"K\u00f6del","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Camelia M.","family":"Monoranu","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Karl H.","family":"Plate","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Sven","family":"Hammerschmidt","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Roland","family":"Nau","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Kavi","family":"Devraj","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-3321-7551","authenticated-orcid":false,"given":"Volkhard A. 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