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Meningitic <jats:italic>E. coli<\/jats:italic> infection is often accompanied by an elevated blood\u2013brain barrier (BBB) permeability. BBB is the structural and functional barrier composed of brain microvascular endothelial cells (BMECs), astrocytes, and pericytes, and we have previously shown that astrocytes-derived TGF\u03b21 physiologically maintained the BBB permeability by triggering a non-canonical hedgehog signaling in brain microvascular endothelial cells (BMECs). Here, we subsequently demonstrated that meningitic <jats:italic>E. coli<\/jats:italic> infection could subvert this intercellular communication within BBB by attenuating TGFBRII\/Gli2-mediated such signaling. By high-throughput screening, we identified <jats:italic>E. coli<\/jats:italic> \u03b1-hemolysin as the critical determinant responsible for this attenuation through Sp1-dependent TGFBRII reduction and triggering Ca<jats:sup>2+<\/jats:sup> influx and protein kinase A activation, thus leading to Gli2 suppression. Additionally, the exogenous hedgehog agonist SAG exhibited promising protection against the infection<jats:italic>-<\/jats:italic>caused BBB dysfunction. Our work revealed a hedgehog-targeted pathogenic mechanism during meningitic <jats:italic>E. coli<\/jats:italic>-caused BBB disruption and suggested that activating hedgehog signaling within BBB could be a potential protective strategy for future therapy of bacterial meningitis.<\/jats:p>","DOI":"10.1186\/s13041-021-00826-2","type":"journal-article","created":{"date-parts":[[2021,7,19]],"date-time":"2021-07-19T07:02:59Z","timestamp":1626678179000},"update-policy":"https:\/\/doi.org\/10.1007\/springer_crossmark_policy","source":"Crossref","is-referenced-by-count":24,"title":["Meningitic Escherichia coli \u03b1-hemolysin aggravates blood\u2013brain barrier disruption via targeting TGF\u03b21-triggered hedgehog signaling"],"prefix":"10.1186","volume":"14","author":[{"given":"Jiyang","family":"Fu","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Liang","family":"Li","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Dong","family":"Huo","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Ruicheng","family":"Yang","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Bo","family":"Yang","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Bojie","family":"Xu","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Xiaopei","family":"Yang","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Menghong","family":"Dai","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Chen","family":"Tan","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Huanchun","family":"Chen","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-0191-1378","authenticated-orcid":false,"given":"Xiangru","family":"Wang","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"297","published-online":{"date-parts":[[2021,7,19]]},"reference":[{"issue":"10063","key":"826_CR1","doi-asserted-by":"publisher","first-page":"3036","DOI":"10.1016\/S0140-6736(16)30654-7","volume":"388","author":"F McGill","year":"2016","unstructured":"McGill F, Heyderman RS, Panagiotou S, Tunkel AR, Solomon T. 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