{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,9,26]],"date-time":"2026-09-26T21:41:42Z","timestamp":1790458902744,"version":"4.1.0"},"reference-count":63,"publisher":"Public Library of Science (PLoS)","issue":"3","license":[{"start":{"date-parts":[[2021,3,24]],"date-time":"2021-03-24T00:00:00Z","timestamp":1616544000000},"content-version":"vor","delay-in-days":0,"URL":"http:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"DOI":"10.13039\/100010769","name":"Petrus och Augusta Hedlunds Stiftelse","doi-asserted-by":"publisher","id":[{"id":"10.13039\/100010769","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/100008738","name":"Jeanssons Stiftelser","doi-asserted-by":"publisher","id":[{"id":"10.13039\/100008738","id-type":"DOI","asserted-by":"publisher"}]},{"name":"\u00c5ke Wiberg Stiftelse"},{"name":"SFO StratNeuro"},{"DOI":"10.13039\/501100006350","name":"Stiftelsen Clas Groschinskys Minnesfond","doi-asserted-by":"publisher","id":[{"id":"10.13039\/501100006350","id-type":"DOI","asserted-by":"publisher"}]},{"name":"Karolinska Institutet (SE), Faculty Board"},{"DOI":"10.13039\/501100004047","name":"Karolinska Institutet","doi-asserted-by":"publisher","award":["Research Foundation Grants"],"award-info":[{"award-number":["Research Foundation Grants"]}],"id":[{"id":"10.13039\/501100004047","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/501100004359","name":"Vetenskapsr\u00e5det","doi-asserted-by":"publisher","id":[{"id":"10.13039\/501100004359","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/501100004063","name":"Knut och Alice Wallenbergs Stiftelse","doi-asserted-by":"publisher","id":[{"id":"10.13039\/501100004063","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/501100004348","name":"Stockholm County Council","doi-asserted-by":"crossref","id":[{"id":"10.13039\/501100004348","id-type":"DOI","asserted-by":"crossref"}]},{"DOI":"10.13039\/501100001729","name":"Stiftelsen f\u00f6r\u00a0Strategisk Forskning","doi-asserted-by":"publisher","id":[{"id":"10.13039\/501100001729","id-type":"DOI","asserted-by":"publisher"}]}],"content-domain":{"domain":["www.plospathogens.org"],"crossmark-restriction":false},"short-container-title":["PLoS Pathog"],"abstract":"<jats:p>\n                    Neuronal damage is a major consequence of bacterial meningitis, but little is known about mechanisms of bacterial interaction with neurons leading to neuronal cell death.\n                    <jats:italic>Streptococcus pneumoniae<\/jats:italic>\n                    (pneumococcus) is a leading cause of bacterial meningitis and many survivors develop neurological sequelae after the acute infection has resolved, possibly due to neuronal damage. Here, we studied mechanisms for pneumococcal interactions with neurons. Using human primary neurons, pull-down experiments and mass spectrometry, we show that pneumococci interact with the cytoskeleton protein \u03b2-actin through the pilus-1 adhesin RrgA and the cytotoxin pneumolysin (Ply), thereby promoting adhesion and invasion of neurons, and neuronal death. Using our bacteremia-derived meningitis mouse model, we observe that RrgA- and Ply-expressing pneumococci co-localize with neuronal \u03b2-actin. Using purified proteins, we show that Ply, through its cholesterol-binding domain 4, interacts with the neuronal plasma membrane, thereby increasing the exposure on the outer surface of \u03b2-actin filaments, leading to more \u03b2-actin binding sites available for RrgA binding, and thus enhanced pneumococcal interactions with neurons. Pneumococcal infection promotes neuronal death possibly due to increased intracellular Ca\n                    <jats:sup>2+<\/jats:sup>\n                    levels depending on presence of Ply, as well as on actin cytoskeleton disassembly. STED super-resolution microscopy showed disruption of \u03b2-actin filaments in neurons infected with pneumococci expressing RrgA and Ply. Finally, neuronal death caused by pneumococcal infection could be inhibited using antibodies against \u03b2-actin. The generated data potentially helps explaining mechanisms for why pneumococci frequently cause neurological sequelae.\n                  <\/jats:p>","DOI":"10.1371\/journal.ppat.1009432","type":"journal-article","created":{"date-parts":[[2021,3,24]],"date-time":"2021-03-24T13:32:11Z","timestamp":1616592731000},"page":"e1009432","update-policy":"https:\/\/doi.org\/10.1371\/journal.ppat.corrections_policy","source":"Crossref","is-referenced-by-count":38,"title":["Neuronal death in pneumococcal meningitis is triggered by pneumolysin and RrgA interactions with \u03b2-actin"],"prefix":"10.1371","volume":"17","author":[{"ORCID":"https:\/\/orcid.org\/0000-0001-5897-4383","authenticated-orcid":true,"given":"Mahebali","family":"Tabusi","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-6844-401X","authenticated-orcid":true,"given":"Sigrun","family":"Thorsdottir","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Maria","family":"Lysandrou","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-1316-3856","authenticated-orcid":true,"given":"Ana Rita","family":"Narciso","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Melania","family":"Minoia","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Chinmaya Venugopal","family":"Srambickal","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-3200-0374","authenticated-orcid":true,"given":"Jerker","family":"Widengren","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Birgitta","family":"Henriques-Normark","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-5249-9120","authenticated-orcid":true,"given":"Federico","family":"Iovino","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"340","published-online":{"date-parts":[[2021,3,24]]},"reference":[{"issue":"4","key":"ppat.1009432.ref001","doi-asserted-by":"crossref","first-page":"307","DOI":"10.1016\/j.tim.2015.12.012","article-title":"How does Streptococcus pneumoniae invade the brain?","volume":"24","author":"F Iovino","year":"2016","journal-title":"Trends Microbiol"},{"issue":"3","key":"ppat.1009432.ref002","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":"1","key":"ppat.1009432.ref003","doi-asserted-by":"crossref","first-page":"44","DOI":"10.1056\/NEJMra052116","article-title":"Community-acquired bacterial meningitis in adults","volume":"354","author":"D van de Beek","year":"2006","journal-title":"N Eng J Med"},{"issue":"18","key":"ppat.1009432.ref004","doi-asserted-by":"crossref","first-page":"1849","DOI":"10.1056\/NEJMoa040845","article-title":"Clinical features and prognostic factors in adults with bacterial meningitis","volume":"351","author":"D van de Beek","year":"2004","journal-title":"N Eng J Med"},{"issue":"1","key":"ppat.1009432.ref005","doi-asserted-by":"crossref","first-page":"18","DOI":"10.1016\/j.jinf.2016.04.009","article-title":"Neurological sequelae of bacterial meningitis","volume":"73","author":"MJ Lucas","year":"2016","journal-title":"J Infect"},{"issue":"Pt 2","key":"ppat.1009432.ref006","doi-asserted-by":"crossref","first-page":"333","DOI":"10.1093\/brain\/awh711","article-title":"Neuropsychological sequelae of bacterial and viral meningitis","volume":"129","author":"H Schmidt","year":"2006","journal-title":"Brain"},{"issue":"1","key":"ppat.1009432.ref007","doi-asserted-by":"crossref","first-page":"3","DOI":"10.1097\/INF.0b013e3181ef25f7","article-title":"Long-term sequelae of childhood bacterial meningitis: an underappreciated problem","volume":"30","author":"A Chandran","year":"2011","journal-title":"Pediatr Infect Dis J"},{"issue":"1","key":"ppat.1009432.ref008","doi-asserted-by":"crossref","first-page":"38","DOI":"10.1016\/S0166-2236(00)02024-5","article-title":"Neuronal injury in bacterial meningitis: mechanisms and implications for therapy","volume":"25","author":"R Nau","year":"2002","journal-title":"Trends Neurosci"},{"issue":"8","key":"ppat.1009432.ref009","doi-asserted-by":"crossref","first-page":"2821","DOI":"10.1172\/JCI84705","article-title":"Pneumococcal meningitis is promoted by single cocci expressing pilus adhesin RrgA","volume":"126","author":"F Iovino","year":"2016","journal-title":"J Clin Invest"},{"issue":"7","key":"ppat.1009432.ref010","doi-asserted-by":"crossref","first-page":"e68408","DOI":"10.1371\/journal.pone.0068408","article-title":"Interactions between blood-borne Streptococcus pneumoniae and the blood-brain barrier preceding meningitis","volume":"8","author":"F Iovino","year":"2013","journal-title":"PloS One"},{"issue":"8","key":"ppat.1009432.ref011","doi-asserted-by":"crossref","first-page":"2857","DOI":"10.1073\/pnas.0511017103","article-title":"A pneumococcal pilus influences virulence and host inflammatory responses","volume":"103","author":"MA Barocchi","year":"2006","journal-title":"Proc Natl Acad Sci U S A"},{"issue":"2","key":"ppat.1009432.ref012","doi-asserted-by":"crossref","first-page":"329","DOI":"10.1111\/j.1365-2958.2007.05908.x","article-title":"RrgA is a pilus-associated adhesin in Streptococcus pneumoniae","volume":"66","author":"AL Nelson","year":"2007","journal-title":"Mol Microbiol"},{"issue":"2","key":"ppat.1009432.ref013","doi-asserted-by":"crossref","first-page":"195","DOI":"10.1111\/j.1365-2249.2004.02611.x","article-title":"O\u00b4callaghan C, Andrew PA. The role of pneumolysin in pneumococcal pneumonia and meningitis","volume":"138","author":"RA Hirst","year":"2004","journal-title":"Clin Exp Immunol"},{"issue":"1","key":"ppat.1009432.ref014","doi-asserted-by":"crossref","first-page":"19","DOI":"10.1172\/JCI12035","article-title":"Pneumococcal pneumolysin and H(2)O(2) mediate brain cell apoptosis during meningitis","volume":"109","author":"JS Braun","year":"2002","journal-title":"J Clin Invest"},{"issue":"1","key":"ppat.1009432.ref015","doi-asserted-by":"crossref","first-page":"62","DOI":"10.1038\/s41564-018-0280-x","article-title":"Pneumolysin Binds to the Mannose Receptor C Type 1 (MRC-1) Leading to Anti-Inflammatory Responses and Enhanced Pneumococcal Survival.","volume":"4","author":"K Subramanian","year":"2019","journal-title":"Nat Microbiol"},{"issue":"6","key":"ppat.1009432.ref016","doi-asserted-by":"crossref","first-page":"1619","DOI":"10.1084\/jem.20161668","article-title":"pIgR and PECAM-1 bind to pneumococcal adhesins RrgA and PspC mediating bacterial brain invasion","volume":"214","author":"F Iovino","year":"2017","journal-title":"J Exp Med"},{"issue":"6","key":"ppat.1009432.ref017","doi-asserted-by":"crossref","first-page":"598","DOI":"10.1038\/mi.2011.37","article-title":"Regulation of the Polymeric Immunoglobulin Receptor and IgA Transport: New Advances in Environmental Factors That Stimulate pIgR Expression and Its Role in Mucosal Immunity","volume":"4","author":"FE Johansen","year":"2011","journal-title":"Mucosal Immunol"},{"issue":"6","key":"ppat.1009432.ref018","doi-asserted-by":"crossref","first-page":"827","DOI":"10.1016\/S0092-8674(00)00071-4","article-title":"The polymeric immunoglobulin receptor translocates pneumococci across human nasopharyngeal epithelial cells","volume":"102","author":"JR Zhang","year":"2000","journal-title":"Cell"},{"key":"ppat.1009432.ref019","volume-title":"Molecular Medicine","author":"M Krauss","year":"2005"},{"issue":"9","key":"ppat.1009432.ref020","doi-asserted-by":"crossref","first-page":"jcs215509","DOI":"10.1242\/jcs.215509","article-title":"The making of the \u2018actin code\u2019: regulation of the actin\u2019s biological function at the aminoacid and nucleotide level","volume":"131","author":"P Vedula","year":"2018","journal-title":"J Cell Sci"},{"key":"ppat.1009432.ref021","doi-asserted-by":"crossref","first-page":"35","DOI":"10.1016\/S0074-7696(01)02003-4","article-title":"Functional specificity of actin isoforms","volume":"202","author":"SY Khaitlina","year":"2001","journal-title":"Int Rev Cytol"},{"issue":"21","key":"ppat.1009432.ref022","doi-asserted-by":"crossref","first-page":"4047","DOI":"10.1091\/mbc.e11-06-0582","article-title":"\u03b2-actin specifically controls cell growth, migration, and the G-actin pool","volume":"22","author":"TM Bunnell","year":"2011","journal-title":"Mol Biol Cell"},{"issue":"1","key":"ppat.1009432.ref023","doi-asserted-by":"crossref","first-page":"7","DOI":"10.1083\/jcb.201103148","article-title":"Pathogens and polymers: Microbe\u2013host interactions illuminate the cytoskeleton","volume":"195","author":"CM Haglund","year":"2011","journal-title":"J Cell Biol"},{"issue":"50","key":"ppat.1009432.ref024","doi-asserted-by":"crossref","first-page":"11291","DOI":"10.1523\/JNEUROSCI.3443-04.2004","article-title":"Role of actin filaments in the axonal tranport of microtubules","volume":"24","author":"PT Hasaka","year":"2004","journal-title":"J Neurosci"},{"issue":"5801","key":"ppat.1009432.ref025","doi-asserted-by":"crossref","first-page":"985","DOI":"10.1126\/science.1133174","article-title":"Microtubule-severing activity of Shigella is pivotal for intracellular spreading","volume":"314","author":"S Yoshida","year":"2006","journal-title":"Science"},{"issue":"1","key":"ppat.1009432.ref026","doi-asserted-by":"crossref","first-page":"26","DOI":"10.1038\/nrmicro2265","article-title":"Molecular mechanisms of Escherichia coli pathogenicity","volume":"8","author":"MA Croxen","year":"2010","journal-title":"Nat Rev Microbiol"},{"issue":"1","key":"ppat.1009432.ref027","first-page":"e02030","article-title":"Dissecting bacterial cell wall entry and signaling in aukaryotic cells: an actin-dependent pathway parallels platelet-activating factor receptor-mediated endocytosis","volume":"8","author":"LN Loh","year":"2017"},{"issue":"3","key":"ppat.1009432.ref028","doi-asserted-by":"crossref","first-page":"636","DOI":"10.1016\/j.jmb.2012.11.034","article-title":"Direct transmembrane interaction between actin and the pore-competent cholesterol-dependent cytolysin pneumolysin","volume":"425","author":"S Hupp","year":"2013","journal-title":"J Mol Biol"},{"issue":"108","key":"ppat.1009432.ref029","first-page":"53193","article-title":"Differentiation of the SH-SY5Y human neuroblastoma cell line","author":"MM Shipley","year":"2016","journal-title":"J Vis Exp"},{"issue":"6","key":"ppat.1009432.ref030","doi-asserted-by":"crossref","first-page":"1841","DOI":"10.1016\/S0002-9440(10)62493-5","article-title":"Microtubule-associated Protein 2, a Marker of Neuronal Differentiation, Induces Mitotic Defects, Inhibits Growth of Melanoma Cells, and Predicts Metastatic Potential of Cutaneous Melanoma","volume":"166","author":"MH Soltani","year":"2005","journal-title":"Am J Pathol"},{"key":"ppat.1009432.ref031","doi-asserted-by":"crossref","first-page":"125","DOI":"10.1007\/978-94-017-7215-0_9","article-title":"Neuron-specific enolase as a biomarker: biochemical and clinical aspects","volume":"867","author":"MA Isgr\u00f2","year":"2015","journal-title":"Adv Exp Med Biol"},{"key":"ppat.1009432.ref032","doi-asserted-by":"crossref","first-page":"157","DOI":"10.1016\/B978-0-12-407704-1.00004-X","article-title":"Actin isoforms in neuronal development and function","volume":"301","author":"TR Cheever","year":"2013","journal-title":"Int Rev Cell Mol Biol"},{"issue":"3","key":"ppat.1009432.ref033","doi-asserted-by":"crossref","first-page":"1102","DOI":"10.1016\/j.bbamem.2012.12.004","article-title":"Actin filaments attachment at the plasma membrane in live cells cause formation of ordered lipid domains","volume":"1828","author":"J Dinic","year":"2013","journal-title":"Biochim Biophys Acta"},{"issue":"Pt 21","key":"ppat.1009432.ref034","doi-asserted-by":"crossref","first-page":"3685","DOI":"10.1242\/jcs.113.21.3685","article-title":"The Actin Cytoskeleton and Plasma Membrane Connection: PtdIns(4,5)P(2) Influences Cytoskeletal Protein Activity at the Plasma Membrane","volume":"113","author":"AS Sechi","year":"2000","journal-title":"J Cell Sci"},{"issue":"4","key":"ppat.1009432.ref035","doi-asserted-by":"crossref","first-page":"653","DOI":"10.1083\/jcb.112.4.653","article-title":"Beta Actin and Its mRNA Are Localized at the Plasma Membrane and the Regions of Moving Cytoplasm During the Cellular Response to Injury","volume":"112","author":"TC Hoock","year":"1991","journal-title":"J Cell Biol"},{"issue":"2","key":"ppat.1009432.ref036","doi-asserted-by":"crossref","first-page":"981","DOI":"10.1523\/JNEUROSCI.15-02-00981.1995","article-title":"Motility and cytoskeletal organization of migrating cerebellar granule neurons","volume":"15","author":"RJ Rivas","year":"1995","journal-title":"J Neurosci"},{"issue":"15","key":"ppat.1009432.ref037","doi-asserted-by":"crossref","first-page":"R677","DOI":"10.1016\/j.cub.2015.06.020","article-title":"Coordinating neuronal actin-microtubule dynamics","volume":"25","author":"CH Coles","year":"2015","journal-title":"Curr Biol"},{"issue":"12","key":"ppat.1009432.ref038","doi-asserted-by":"crossref","first-page":"9526","DOI":"10.1074\/jbc.M007333200","article-title":"Activation of anaplastic lymphoma kinase receptor tyrosine kinase induces neuronal differentiation through the mitogen-activated protein kinase pathway","volume":"276","author":"B Souttou","year":"2001","journal-title":"J Biol Chem"},{"issue":"3","key":"ppat.1009432.ref039","doi-asserted-by":"crossref","first-page":"75","DOI":"10.4161\/bioa.20975","article-title":"The actin cytoskeleton as a sensor and mediator of apoptosis","volume":"2","author":"M Desouza","year":"2012","journal-title":"Bioarchtecture"},{"issue":"2","key":"ppat.1009432.ref040","doi-asserted-by":"crossref","first-page":"247","DOI":"10.1016\/j.cell.2005.02.033","article-title":"Structural basis of pore formation by the bacterial toxin pneumolysin","volume":"121","author":"SJ Tilley","year":"2005","journal-title":"Cell"},{"key":"ppat.1009432.ref041","doi-asserted-by":"crossref","first-page":"13293","DOI":"10.1038\/srep13293","article-title":"The crystal structure of pneumolysin at 2.0 \u00c5 resolution reveals molecular packing of the pre-pore complex","volume":"5","author":"JE Marshall","year":"2015","journal-title":"Sci Rep"},{"key":"ppat.1009432.ref042","doi-asserted-by":"crossref","first-page":"13352","DOI":"10.1073\/pnas.1904304116","article-title":"Membrane performation by the pore-forming toxin pneumolysin","volume":"2116\/27","author":"M V\u00f6gele","year":"2019","journal-title":"PNAS"},{"issue":"Pt 2","key":"ppat.1009432.ref043","doi-asserted-by":"crossref","first-page":"543","DOI":"10.1113\/jphysiol.2006.114108","article-title":"Calcium channel and glutamate receptor activities regulate actin organization in salamander retinal neurons","volume":"575","author":"M Cristofanilli","year":"2006","journal-title":"J Physiol"},{"key":"ppat.1009432.ref044","doi-asserted-by":"crossref","first-page":"29","DOI":"10.1016\/j.mcn.2017.07.006","article-title":"How does calcium interact with the cytoskeleton to regulate growth cone motility during axon pathfinding?","volume":"84","author":"RJ Gasperini","year":"2017","journal-title":"Mol Cell Neurosci"},{"key":"ppat.1009432.ref045","doi-asserted-by":"crossref","first-page":"34","DOI":"10.1016\/j.ceca.2017.10.003","article-title":"Differential cytotoxicity and intracellular calcium-signalling following activation of the calcium-permeable ion channels TRPV1 and TRPA1","volume":"68","author":"T Stueber","year":"2017","journal-title":"Cell Calcium"},{"issue":"Suppl 1Suppl 1","key":"ppat.1009432.ref046","first-page":"25","article-title":"Calcium signaling and cytotoxicity","volume":"107","author":"GE Kass","year":"1999","journal-title":"Environ Health Perspect"},{"issue":"2","key":"ppat.1009432.ref047","doi-asserted-by":"crossref","first-page":"325","DOI":"10.1016\/0006-8993(88)90941-9","article-title":"Calcium-dependent glutamate cytotoxicity in a neuronal cell line","volume":"444","author":"TH Murphy","journal-title":"Brain Res"},{"issue":"Pt 2","key":"ppat.1009432.ref048","doi-asserted-by":"crossref","first-page":"221","DOI":"10.1111\/j.1469-7793.2000.t01-2-00221.x","article-title":"The actin cytoskeleton in store-mediated calcium entry","volume":"526","author":"JA Rosado","year":"2000","journal-title":"J Physiol"},{"issue":"6","key":"ppat.1009432.ref049","doi-asserted-by":"crossref","first-page":"1975","DOI":"10.1083\/jcb.110.6.1975","article-title":"Actin assembly in electropermeabilized neutrophils: role of intracellular calcium","volume":"110","author":"GP Downey","year":"1990","journal-title":"J Cell Biol"},{"issue":"2","key":"ppat.1009432.ref050","first-page":"e00559","article-title":"Immunomodulatory effects of pneumococcal extracellular vesicles on cellular and humoral host defenses. Mbio","volume":"9","author":"M Codemo","year":"2018"},{"issue":"1","key":"ppat.1009432.ref051","doi-asserted-by":"crossref","first-page":"106","DOI":"10.1016\/j.str.2009.10.019","article-title":"Structural basis of host cell recognition by the pilus adhesin from Streptococcus pneumoniae","volume":"18","author":"T Izor\u00e9","year":"2010","journal-title":"Structure"},{"issue":"Pt 2","key":"ppat.1009432.ref052","doi-asserted-by":"crossref","first-page":"199","DOI":"10.1242\/jcs.018564","article-title":"Integrins in cell migration-the actin connection","volume":"122","author":"M Vicente-Manzanares","year":"2009","journal-title":"J Cell Sci"},{"issue":"3","key":"ppat.1009432.ref053","doi-asserted-by":"crossref","first-page":"242","DOI":"10.1016\/j.cub.2005.12.033","article-title":"Purified integrin adhesion complexes exhibit actin-polymerization activity","volume":"16","author":"B Butler","year":"2006","journal-title":"Curr Biol"},{"issue":"1","key":"ppat.1009432.ref054","doi-asserted-by":"crossref","first-page":"e00535","DOI":"10.1128\/mBio.00535-12","article-title":"Pilus adhesin RrgA interacts with complement receptor 3, thereby affecting macrophage function and systemic pneumococcal disease","volume":"4","author":"S Orrskog","year":"2012","journal-title":"Mbio"},{"issue":"12","key":"ppat.1009432.ref055","doi-asserted-by":"crossref","first-page":"5033","DOI":"10.1128\/IAI.00601-10","article-title":"The two variants of the Streptococcus pneumoniae pilus 1 RrgA adhesin retain the same function and elicit cross-protection in vivo","volume":"78","author":"M Moschioni","year":"2010","journal-title":"Infect Immun"},{"issue":"3","key":"ppat.1009432.ref056","doi-asserted-by":"crossref","first-page":"650","DOI":"10.1111\/mmi.14451","article-title":"The impact of the ancillary pilus-1 protein RrgA of Streptococcus pneumoniae on colonization and disease","volume":"113","author":"F Iovino","year":"2020","journal-title":"Mol Microbiol"},{"issue":"2","key":"ppat.1009432.ref057","doi-asserted-by":"crossref","first-page":"532","DOI":"10.1016\/j.bbamem.2013.07.018","article-title":"Interaction of membrane\/lipid rafts with the cytoskeleton: impact on signaling and function: membrane\/lipid rafts, mediators of cytoskeletal arrangement and cell signaling","volume":"1838","author":"PB Head","year":"2014","journal-title":"Biochim Biophys Acta"},{"issue":"3","key":"ppat.1009432.ref058","doi-asserted-by":"crossref","first-page":"355","DOI":"10.1006\/nbdi.2002.0561","article-title":"Neurotoxicity of pneumolysin, a major pneumococcal virulence factor, involves calcium influx and depends on activation of p38 mitogen-activated protein kinase","volume":"11","author":"AK Stringaris","year":"2002","journal-title":"Neurobiol Dis"},{"issue":"9","key":"ppat.1009432.ref059","doi-asserted-by":"crossref","first-page":"4245","DOI":"10.1128\/IAI.00031-07","article-title":"Pneumolysin causes neuronal cell death through mitochondrial damage","volume":"75","author":"JS Braun","year":"2007","journal-title":"Infect Immun"},{"issue":"8","key":"ppat.1009432.ref060","doi-asserted-by":"crossref","first-page":"2897","DOI":"10.1073\/pnas.0608213104","article-title":"Cholesterol-dependent actin remodeling via RhoA and Rac1 activation by Streptococcus pneumonie toxin pneumolysin","volume":"20104","author":"AI Iliev","year":"2007","journal-title":"PNAS."},{"issue":"3","key":"ppat.1009432.ref061","doi-asserted-by":"crossref","first-page":"476","DOI":"10.1093\/infdis\/jiy193","article-title":"Receptor blockade: a novel approach to protect the brain from pneumococcal invasion","volume":"218","author":"F Iovino","year":"2018","journal-title":"J Infect Dis"},{"issue":"6787","key":"ppat.1009432.ref062","doi-asserted-by":"crossref","first-page":"694","DOI":"10.1038\/35015091","article-title":"Alpha-haemolysin of uropathogenic E. coli induces Ca2+ oscillations in renal epithelial cells","volume":"405","author":"P Uhl\u00e9n","year":"2000","journal-title":"Nature"},{"issue":"9","key":"ppat.1009432.ref063","doi-asserted-by":"crossref","first-page":"3555","DOI":"10.1128\/IAI.00046-14","article-title":"Platelet endothelial cell adhesion molecule-1, a putative receptor for the adhesion of Streptococcus pneumoniae to the vascular endothelium of the blood-brain barrier","volume":"82","author":"F Iovino","year":"2014","journal-title":"Infect Immun"}],"container-title":["PLOS Pathogens"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/dx.plos.org\/10.1371\/journal.ppat.1009432","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2021,4,30]],"date-time":"2021-04-30T00:02:58Z","timestamp":1619740978000},"score":1,"resource":{"primary":{"URL":"https:\/\/dx.plos.org\/10.1371\/journal.ppat.1009432"}},"subtitle":[],"editor":[{"given":"Carlos Javier","family":"Orihuela","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"editor"}]}],"short-title":[],"issued":{"date-parts":[[2021,3,24]]},"references-count":63,"journal-issue":{"issue":"3","published-online":{"date-parts":[[2021,3,24]]}},"URL":"https:\/\/doi.org\/10.1371\/journal.ppat.1009432","relation":{"has-preprint":[{"id-type":"doi","id":"10.1101\/2020.08.20.258681","asserted-by":"object"}]},"ISSN":["1553-7374"],"issn-type":[{"value":"1553-7374","type":"electronic"}],"subject":[],"published":{"date-parts":[[2021,3,24]]}}}