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dc.contributor.authorStark, Anne-Katrien
dc.contributor.authorChandra, Anita
dc.contributor.authorChakraborty, Krishnendu
dc.contributor.authorAlam, Rafeah
dc.contributor.authorCarbonaro, Valentina
dc.contributor.authorClark, Jonathan
dc.contributor.authorSriskantharajah, Srividya
dc.contributor.authorBradley, Glyn
dc.contributor.authorRichter, Alex G
dc.contributor.authorBanham-Hall, Edward
dc.contributor.authorClatworthy, Menna
dc.contributor.authorNezhentsev, Sergey
dc.contributor.authorHamblin, J Nicole
dc.contributor.authorHessel, Edith M
dc.contributor.authorCondliffe, Alison M
dc.contributor.authorOkkenhaug, Klaus
dc.date.accessioned2018-10-10T10:44:39Z
dc.date.available2018-10-10T10:44:39Z
dc.date.issued2018-08-09
dc.identifier.issn2041-1723
dc.identifier.urihttps://www.repository.cam.ac.uk/handle/1810/283518
dc.description.abstractStreptococcus pneumoniae is a major cause of pneumonia and a leading cause of death world-wide. Antibody-mediated immune responses can confer protection against repeated exposure to S. pneumoniae, yet vaccines offer only partial protection. Patients with Activated PI3Kδ Syndrome (APDS) are highly susceptible to S. pneumoniae. We generated a conditional knock-in mouse model of this disease and identify a CD19+B220- B cell subset that is induced by PI3Kδ signaling, resides in the lungs, and is correlated with increased susceptibility to S. pneumoniae during early phases of infection via an antibody-independent mechanism. We show that an inhaled PI3Kδ inhibitor improves survival rates following S. pneumoniae infection in wild-type mice and in mice with activated PI3Kδ. These results suggest that a subset of B cells in the lung can promote the severity of S. pneumoniae infection, representing a potential therapeutic target.
dc.description.sponsorshipWellcome, MRC, BBSRC
dc.format.mediumElectronic
dc.languageeng
dc.publisherSpringer Science and Business Media LLC
dc.rightsAttribution 4.0 International
dc.rights.urihttps://creativecommons.org/licenses/by/4.0/
dc.subjectLung
dc.subjectB-Lymphocytes
dc.subjectNeutrophils
dc.subjectAnimals
dc.subjectMice, Inbred C57BL
dc.subjectHumans
dc.subjectMice
dc.subjectStreptococcus pneumoniae
dc.subjectPneumococcal Infections
dc.subjectAntigens, CD19
dc.subjectInterleukin-10
dc.subjectSignal Transduction
dc.subjectSpecies Specificity
dc.subjectEnzyme Activation
dc.subjectGenotype
dc.subjectFemale
dc.subjectMale
dc.subjectGene Knock-In Techniques
dc.subjectPhosphatidylinositol 3-Kinases
dc.subjectClass I Phosphatidylinositol 3-Kinases
dc.subjectPhosphoinositide-3 Kinase Inhibitors
dc.titlePI3Kδ hyper-activation promotes development of B cells that exacerbate Streptococcus pneumoniae infection in an antibody-independent manner.
dc.typeArticle
prism.issueIdentifier1
prism.publicationDate2018
prism.publicationNameNat Commun
prism.startingPage3174
prism.volume9
dc.identifier.doi10.17863/CAM.30881
dcterms.dateAccepted2018-07-17
rioxxterms.versionofrecord10.1038/s41467-018-05674-8
rioxxterms.licenseref.urihttp://www.rioxx.net/licenses/all-rights-reserved
rioxxterms.licenseref.startdate2018-08-09
dc.contributor.orcidStark, Anne-Katrien [0000-0001-6241-3909]
dc.contributor.orcidChandra, Anita [0000-0002-9061-879X]
dc.contributor.orcidCarbonaro, Valentina [0000-0003-0915-6901]
dc.contributor.orcidClatworthy, Menna [0000-0002-3340-9828]
dc.contributor.orcidNezhentsev, Sergey [0000-0002-7528-4461]
dc.contributor.orcidOkkenhaug, Klaus [0000-0002-9432-4051]
dc.identifier.eissn2041-1723
rioxxterms.typeJournal Article/Review
pubs.funder-project-idWellcome Trust (103413/Z/13/Z)
pubs.funder-project-idWellcome Trust (206618/Z/17/Z)
pubs.funder-project-idMedical Research Council (MR/M012328/1)
pubs.funder-project-idWellcome Trust (095198/Z/10/Z)
pubs.funder-project-idMedical Research Council (MR/N024907/1)
pubs.funder-project-idArthritis Research UK (21777)
cam.issuedOnline2018-08-09


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Attribution 4.0 International
Except where otherwise noted, this item's licence is described as Attribution 4.0 International