{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,10,11]],"date-time":"2026-10-11T12:51:13Z","timestamp":1791723073487,"version":"4.3.4"},"update-to":[{"DOI":"10.1371\/journal.ppat.1009152","type":"new_version","label":"New version","source":"publisher","updated":{"date-parts":[[2021,1,8]],"date-time":"2021-01-08T00:00:00Z","timestamp":1610064000000}}],"reference-count":65,"publisher":"Public Library of Science (PLoS)","issue":"12","license":[{"start":{"date-parts":[[2020,12,28]],"date-time":"2020-12-28T00:00:00Z","timestamp":1609113600000},"content-version":"vor","delay-in-days":0,"URL":"http:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"content-domain":{"domain":["www.plospathogens.org"],"crossmark-restriction":false},"short-container-title":["PLoS Pathog"],"abstract":"<jats:p><jats:italic>Streptococcus pneumoniae<\/jats:italic>or pneumococcus (PN) is a major causative agent of bacterial meningitis with high mortality in young infants and elderly people worldwide. The mechanism underlying PN crossing of the blood brain barrier (BBB) and specifically, the role of non-endothelial cells of the neurovascular unit that control the BBB function, remains poorly understood. Here, we show that the astroglial connexin 43 (aCx43), a major gap junctional component expressed in astrocytes, plays a predominant role during PN meningitis. Following intravenous PN challenge, mice deficient for aCx43 developed milder symptoms and showed severely reduced bacterial counts in the brain. Immunofluorescence analysis of brain slices indicated that PN induces the aCx43\u2013dependent destruction of the network of glial fibrillary acid protein (GFAP), an intermediate filament protein specifically expressed in astrocytes and up-regulated in response to brain injury. PN also induced nuclear shrinkage in astrocytes associated with the loss of BBB integrity, bacterial translocation across endothelial vessels and replication in the brain cortex. We found that aCx4-dependent astrocyte damages could be recapitulated using<jats:italic>in vitro<\/jats:italic>cultured cells upon challenge with wild-type PN but not with a<jats:italic>ply<\/jats:italic>mutant deficient for the pore-forming toxin pneumolysin (Ply). Consistently, we showed that purified Ply requires Cx43 to promote host cell plasma membrane permeabilization in a process involving the Cx43-dependent release of extracellular ATP and prolonged increase of cytosolic Ca<jats:sup>2+<\/jats:sup>in host cells. These results point to a critical role for astrocytes during PN meningitis and suggest that the cytolytic activity of the major virulence factor Ply at concentrations relevant to bacterial infection requires co-opting of connexin plasma membrane channels.<\/jats:p>","DOI":"10.1371\/journal.ppat.1009152","type":"journal-article","created":{"date-parts":[[2020,12,28]],"date-time":"2020-12-28T21:13:41Z","timestamp":1609190021000},"page":"e1009152","update-policy":"https:\/\/doi.org\/10.1371\/journal.ppat.corrections_policy","source":"Crossref","is-referenced-by-count":9,"title":["Role of astroglial Connexin 43 in pneumolysin cytotoxicity and during pneumococcal meningitis"],"prefix":"10.1371","volume":"16","author":[{"ORCID":"https:\/\/orcid.org\/0000-0001-9417-2820","authenticated-orcid":true,"given":"Chakir","family":"Bello","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yasmine","family":"Smail","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-1170-0817","authenticated-orcid":true,"given":"Vincent","family":"Sainte-Rose","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Isabelle","family":"Podglajen","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-0102-1826","authenticated-orcid":true,"given":"Alice","family":"Gilbert","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-1859-0315","authenticated-orcid":true,"given":"Vanessa","family":"Moreira","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Fabrice","family":"Chr\u00e9tien","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-5312-8476","authenticated-orcid":true,"given":"Martine","family":"Cohen Salmon","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-3901-2186","authenticated-orcid":true,"given":"Guy","family":"Tran Van Nhieu","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"340","published-online":{"date-parts":[[2020,12,28]]},"reference":[{"issue":"3","key":"ppat.1009152.ref001","doi-asserted-by":"crossref","first-page":"557","DOI":"10.1128\/CMR.00008-11","article-title":"Pathogenesis and pathophysiology of pneumococcal meningitis","volume":"24","author":"BB Mook-Kanamori","year":"2011","journal-title":"Clin Microbiol Rev"},{"issue":"11","key":"ppat.1009152.ref002","article-title":"BloodBrain Barrier Pathology and CNS Outcomes in Streptococcus pneumoniae Meningitis.","volume":"19","author":"B Yau","year":"2018","journal-title":"Int J Mol Sci."},{"issue":"37","key":"ppat.1009152.ref003","doi-asserted-by":"crossref","DOI":"10.1126\/sciimmunol.aav0492","article-title":"The anatomy and immunology of vasculature in the central nervous system","volume":"4","author":"P Mastorakos","year":"2019","journal-title":"Science immunology"},{"issue":"1","key":"ppat.1009152.ref004","doi-asserted-by":"crossref","first-page":"13","DOI":"10.1016\/j.nbd.2009.07.030","article-title":"Structure and function of the blood-brain barrier","volume":"37","author":"NJ Abbott","year":"2010","journal-title":"Neurobiol Dis"},{"issue":"10","key":"ppat.1009152.ref005","doi-asserted-by":"crossref","first-page":"1470","DOI":"10.1111\/j.1462-5822.2011.01661.x","article-title":"How can microbial interactions with the blood-brain barrier modulate astroglial and neuronal function?","volume":"13","author":"DJ Grab","year":"2011","journal-title":"Cell Microbiol"},{"issue":"12","key":"ppat.1009152.ref006","doi-asserted-by":"crossref","first-page":"1939","DOI":"10.1002\/glia.22575","article-title":"Glial influence on the blood brain barrier","volume":"61","author":"JI Alvarez","year":"2013","journal-title":"Glia"},{"key":"ppat.1009152.ref007","doi-asserted-by":"crossref","first-page":"211","DOI":"10.3389\/fncel.2014.00211","article-title":"Astrocytic modulation of blood brain barrier: perspectives on Parkinson's disease.","volume":"8","author":"R Cabezas","year":"2014","journal-title":"Frontiers in cellular neuroscience"},{"key":"ppat.1009152.ref008","article-title":"Astrocytes in the regulation of cerebrovascular functions","author":"M Cohen-Salmon","year":"2020","journal-title":"Glia"},{"issue":"1","key":"ppat.1009152.ref009","doi-asserted-by":"crossref","first-page":"41","DOI":"10.1038\/nrn1824","article-title":"Astrocyte-endothelial interactions at the blood-brain barrier.","volume":"7","author":"NJ 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